Skip to main content

The role of autophagy in viral infections

Abstract

Autophagy is an evolutionarily conserved catabolic cellular process that exerts antiviral functions during a viral invasion. However, co-evolution and co-adaptation between viruses and autophagy have armed viruses with multiple strategies to subvert the autophagic machinery and counteract cellular antiviral responses. Specifically, the host cell quickly initiates the autophagy to degrade virus particles or virus components upon a viral infection, while cooperating with anti-viral interferon response to inhibit the virus replication. Degraded virus-derived antigens can be presented to T lymphocytes to orchestrate the adaptive immune response. Nevertheless, some viruses have evolved the ability to inhibit autophagy in order to evade degradation and immune responses. Others induce autophagy, but then hijack autophagosomes as a replication site, or hijack the secretion autophagy pathway to promote maturation and egress of virus particles, thereby increasing replication and transmission efficiency. Interestingly, different viruses have unique strategies to counteract different types of selective autophagy, such as exploiting autophagy to regulate organelle degradation, metabolic processes, and immune responses. In short, this review focuses on the interaction between autophagy and viruses, explaining how autophagy serves multiple roles in viral infection, with either proviral or antiviral functions.

Highlights

  1. 1.

    This review focuses on the interaction between autophagy and viruses, explaining how autophagy serves multiple roles in viral infection, with either proviral or antiviral functions.

  2. 2.

    Based on different steps of autophagy and the regulation of immune responses by autophagy, this review oversees the role of autophagy in viral replication, maturation, egress and cell–cell spreading.

  3. 3.

    This review provides an important foundation for the development of broad-spectrum antiviral treatment strategies and drugs based on the regulation of autophagy.

Background

Autophagy is an evolutionarily conserved catabolic process of protein and organelle degradation that is essential to maintain cellular homeostasis [1]. Depending on mechanisms for delivery of cargo to lysosomes, autophagy is categorized into the microautophagy and macroautophagy and chaperone-mediated autophagy (CMA). In microautophagy, autophagic cargo is directly sorted into lysosomes. In the CMA, before substrate delivery to lysosomes, recognition sites on the autophagic cargo are required for molecular chaperons binding to form the CMA substrate/chaperon complex. Macroautophagy, which will be discussed in-depth in this review (hereafter referred to as autophagy), involves the formation of autophagosome, the major lysosomal pathway for cytoplasmic components turnover.

Viruses are microbes with simple structures that must parasitize living cells to proliferate. Nevertheless, viruses have far greater diversity than other organisms. By 2019, 14 orders, 143 families, 64 subfamilies, 846 genera and 4,958 species of viruses had been discovered according to the International Committee on Taxonomy of Viruses (ICTV; https://talk.ictvonline.org/) [2]. In general, the life cycle of most viruses comprises several distinct stages: (1) attachment/adsorption, (2) entry, (3) uncoating, (4) mRNA production/transcription, (5) synthesis of viral components, (6) assembly, and (7) release.

As a defense strategy of organisms, autophagy can be triggered to antagonize viral infections by delivering cytoplasmic virions or viral components to lysosomes for degradation. In addition, the degradation also promotes the inflammatory response, antigen presentation, and clearance for pathogen recognition [3]. However, previous studies have shown that some viruses inhibit or evade autophagy, whereas some viruses even hijack the autophagy mechanism or exploit autophagy to circumvent the host immunity mechanisms for their benefit. With the onset of the global COVID-19 epidemic, the relationship between autophagy and viruses has attracted increased scientific attention. Some new discoveries have broadened our understanding of the relationship between autophagy and viruses. Notably, virus-specific induction of autophagy is related to endosomes. A virus can trigger the autophagy-related 8-phosphatidylserine (ATG8-PS) alternative lipidation mechanism, as well as several others, but this remains poorly understood. Based on different steps of autophagy and the regulation of immune responses by autophagy, this review oversees the role of autophagy in viral replication, maturation, egress and cell–cell spreading.

Autophagy

The process and regulation of autophagy

More than 30 ATGs reported to date participate in the following four steps of autophagy:

  1. (1)

    Autophagy initiation

In general, autophagosomes are derived from the isolation membrane (IM) produced on various organelles, including the endoplasmic reticulum (ER), plasma membrane, recycling endosomes, mitochondria, ATG9-vesicles, COPII vesicles, and ER-Golgi intermediate compartment (ERGIC) [4]. Under stress, cellular type III PI3K-Vps34-Beclin1 complex is activated, and type I PI3K-AKT-MTOR signalling pathway is inhibited. Mechanistic target of rapamycin (MTOR) inhibition allows ULK1/ATG1 and FIP200/RB1CC1/ATG17 to re-associate with dephosphorylated ATG13, and also causes mATG9 to redistribute from the trans-Golgi network (TGN) to the late endosome and form a cup-shaped double-layer IM, and dephosphorylate and activate the ULK1-ATG13-FIP200-ATG101 complex, leading to the initiation of autophagy [5]. In parallel, the Beclin1-ATG14L-VPS15-VPS34 complex is activated to generate phosphatidylinositol-3-phosphate (PtdIns3P) on the endomembrane [6]. The PtdIns3P-enriched area on the endomembrane surface is termed phagophore, which provides a platform for the IM nucleation and expansion (Fig. 1) [7].

  1. (2)

    Elongation and closure of the autophagic membrane

Fig. 1
figure 1

The process and regulation of autophagy. Autophagosomes are derived from IM produced on various organelles. Under stress conditions, the type III PI3K-Vps34-Beclin1 complex is activated, and type I PI3K-AKT-MTOR signalling pathway is inhibited. mTOR inhibition allows ULK1 and FIP2000 to re-associate with dephosphorylated ATG13 and also causes mATG9 to redistribute from TGN to the late endosome, thus forming an IM; it also dephosphorylates and activates the ULK1-ATG13-FIP200-Atg101 complex, leading to autophagy initiation. In parallel, the Beclin1-ATG14L-Vps15-Vps34 complex is activated to generate PtdIns3P on the endomembrane. Elongation and closure of the autophagic membrane require two ubiquitin-like conjugation systems. ATG12 is covalently conjugated to ATG5 with the assistance of ATG7 (encodes an E1-like enzyme) and ATG10 (encodes an E2-like enzyme), then binds with ATG16 and multimerizes to form the ATG12-ATG5-ATG16L complex, which forms an E3-like ligase of LC3, which oligomers coat on the surface or tips of phagophore to initiate its elongation and curvature. The second is the ATG8-PE system: The PE is conjugated to pro-LC3 under the continuous action of ATG4, ATG7 and ATG3 to form LC3-II, respectively. LC3-II incorporates itself into the autophagosome membrane to drive the extension and closure. The maturation of autophagosome is mediated by SNARE, Rab GTPase family members, and Tethering factors. Two cognate SNARE complexes, STX17-SNAP29-VAMP8 and YKT6-SNAP29-STX7, mediate autophagosome and lysosome fusion. Tethering factors, such as HOPS trap vesicles, bring the SNARE complex closer to the target membrane during their intracellular transport. HOPS components promote autophagosome-lysosome fusion through interaction with STX17. In addition, Rubicon negatively regulates the endosome or autophagosome maturation through VPS34, ATG14L or interactions with Rab7 and UVRAG, but Rab7 facilitates the binding of the autophagosome to the HOPS complex on the lysosomes through PLEKHM1. UVRAG activates PI3KC3 and C-VPS/HOPS. Finally, engulfed proteins or organelles are degraded by lysosomal enzymes in autolysosomes, and LC3B-II is also degraded and recycled

Two ubiquitin-like conjugation systems are required in this process. The first is the ATG5-ATG12 ubiquitin-like protein conjugation system: ATG12 is covalently conjugated to ATG5 with the assistance of ATG7 (encodes an E1-like enzyme) and ATG10 (encodes an E2-like enzyme). Then, ATG12-ATG5 complex binds ATG16 and multimerizes to form the ATG12-ATG5-ATG16L complex, which forms an E3-like ligase of the microtubule-associated protein L chain 3 (LC3) [8]. The oligomers of E3-like ligase of LC3 coat the surface or tips of phagophores to initiate their elongation and curvature [8].

The second ubiquitin-like conjugation system is the ATG8-phosphatidylethanolamine (PE) system: the PE is conjugated to Pro-LC3 under the continuous action of ATG4, ATG7 and ATG3, respectively. Specifically, Pro-LC3 is cleaved by ATG4 to produce a soluble form of LC3-I (non-lipidated,18 kDa). LC3-I is activated by ATG7 and transferred to ATG3, and then modified into an autophagy-related form of LC3-II (the combined form of PE, 16 kDa). Moreover, LC3 is present in two forms: LC3-I and LC3-II. In unstimulated cells, LC3 is mainly located in the nucleus, with only a small proportion located in the cytoplasm. When autophagy is activated by external stimuli, pro-LC3 is cleaved into LC3-I and LC3-II. LC3-I dissociates in the cytoplasm into a soluble form, while LC3-II incorporates itself into the autophagosome membrane to drive the extension [9] and closure [10] of the membrane. Thus, the net amount of LC3-II is a critical hallmark for monitoring autophagy (Fig. 1).

  1. (3)

    Maturation and fusion with the lysosomes of autophagosomes

The autophagosome undergoes maturation (including cargo material packaging), then gets transported to lysosomes through the cytoskeletal structures, and finally fuses with the lysosome, leading to the formation of autolysosomes. This process is mediated by intracellular proteins involved in the vesicle transport and fusion, especially soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) superfamily members (YKT6, STX17, SNAP29, VAMP3, VAMP7, VAMP8 and VTI1B) [11,12,13,14,15] Rab GTPase family members (RAB7, RAB8B, RAB9, RAB11, RAB23, RAB24 and RAB33) [16,17,18,19,20] and tethering factors (HOPS complex: vacuolar protein sorting 11 (VPS11), Vps16, VPS18, Vps33A, VPS39, and Vps41) [21, 22]. Two cognate SNARE complexes, STX17-SNAP29-VAMP8[13] and YKT6-SNAP29-STX7 [23] function additively in mediating fusion of the autophagosome with lysosome. Tethering factors trap vesicles during their intracellular transportation and bring them closer to the target membrane, thereby further stabilizing the assembly of SNARE to enhance the specificity and efficiency of vesicle fusion [24]. Through synergistic binding with the Rab protein, SNARE and phospholipids, Tethers are recruited to specific membranes [24, 25]. For instance, all HOPS components promote autophagosome-lysosome fusion through interaction with STX17 [26]. In addition, Rubicon negatively regulates the endosome or autophagosome maturation through VPS34, ATG14L or interactions with Rab7 and the ultraviolet radiation resistance-associated gene protein (UVRAG) [27,28,29]. Rab7 facilitates binding of the autophagosome to the HOPS complex on the lysosome through the pleckstrin homology domain-containing family M member 1 (PLEKHM1) [30]. UVRAG, a component of the PI3KC3 complex (VPS34, p150, Beclin1, UVRAG and ATG14L), functions as a guanine nucleotide exchange factor that catalyzes the exchange of GDP for GTP on Rab7, which activates PI3KC3 and C-VPS/HOPS (Fig. 1) [31].

  1. (4)

    Autophagosome degradation and recycling

In autolysosomes, engulfed proteins or organelles are eventually degraded by lysosomal enzymes, and LC3B-II is also degraded and recycled (Fig. 1).

The types of autophagy

On the basis of nutritional status, autophagy can be roughly divided into selective autophagy, under nutrient-rich conditions, and non-selective autophagy, under starvation conditions [32, 33]. The non-selective autophagy is conserved and mediated by the ULK1/2 complex [34]. Selective autophagy, which is mediated by specific receptors, can be further divided into the ubiquitin-dependent and independent autophagy [35]. Ubiquitin-dependent selective autophagy involves a group of sequestosome-like receptors (SLRs) [36], including p62/SQSTM1 [37], neighbor of BRCA1 gene 1 (NBR1) [38], TAX1BP1 [39], calcium-binding and coiled-coil domain-containing protein 2 (CALCOCO2/NDP52) [40], optineurin, CCDC50 [41] and CCPG1 [42]. Ubiquitin-independent selective autophagy directly targets cargo to ATG8-containing autophagosome membranes; receptors such as BNIP3 [43], PHB2 [44], NIX/BNIP3L [43], FAM134B [45], FUNDC1 [46], TBC1D5 [47], STBD1 [48] and a newly discovered UIM-type autophagy receptor [49] are involved in this process. Furthermore, selective autophagy targets not only pathogenic microorganisms but also specific cellular components and organelles, and has been well characterized and classified according to the type of targeted cargo. For instance, aggrephagy (protein aggregates), ER-phagy or reticulophagy (endoplasmic reticulum), lipophagy (lipid droplets), mitophagy (mitochondria), nucleophagy (nuclei), lysophagy (lysosomes), pexophagy (peroxisomes), ferritinophagy (ferritin), and xenophagy (intracellular pathogens including bacteria, fungi and viruses) (Fig. 2).

Fig. 2
figure 2

The types of autophagy. autophagy can be divided into selective autophagy and non-selective autophagy according to nutritional status. Selective autophagy, which is mediated by specific receptors, can be further divided into the ubiquitin-dependent and independent autophagy. Furthermore, selective autophagy has been well characterized and classified according to the type of targeted cargo. For instance, nucleophagy (nuclei), ferritinophagy (ferritin), pexophagy (peroxisomes), lysophagy (lysosomes), xenophagy (intracellular pathogens including bacteria, fungi and viruses), mitophagy (mitochondria), lipophagy (lipid droplets), reticulophagy (endoplasmic reticulum), aggrephagy (protein aggregates)

As opposed to the canonical autophagy, non-canonical autophagy precedes the formation of autophagosomes [50], which means that lipidated LC3 is inserted into single membranes, especially the endolysosomal membrane, during the process of cellular engulfing of foreign bodies, such as LC3-associated phagocytosis (LAP) [51]. A proportion of the receptor signalling allows cargo to be recruited to the single membrane vesicle, which leads to its labelling with lipidated LC3-PE. Mechanically, non-canonical autophagy may bypass some steps of canonical autophagy during the formation of functional autophagosomes. For instance, it may bypass proteins that are critical for nucleation (Beclin1) and initiation (ULK1), and other proteins involved in elongation and closure (ATG7, ATG5) [52].

There exists another autophagy type: secretory autophagy, which exerts biological functions in the unconventional secretion of leaderless cytosolic proteins [53]. As opposed to proteins that have the N-terminal leader peptides, leaderless cytosolic proteins cannot get into the regular secretory pathway normally operating through the Golgi apparatus and ER [54].

Viruses manipulate the autophagy process

Virus-mediated autophagy initiation

Viral infection induces autophagy initiation

Any steps of the viral life cycle or exposure to viral proteins may trigger autophagy (Fig. 3). Below, we describe several representative examples to illustrate how viruses induce the initiation of autophagy.

Fig. 3
figure 3

Viruses manipulate the autophagy process. Viruses and viral proteins induce autophagy initiation at different stages of the viral life cycle. In the adsorption stage, MEV combines with CD46-Cyt-1, which is linked to VPS34/Beclin1 complex through the interaction with the GOPC, promoting the formation of autophagosomes. LRV activate TLR3 and TRIF to trigger ATG5-mediated autophagy; ATG5 facilitates the production of TLR9-induced IFN-I in pDCs infected with HSV-1; TLR-7 recognizes RVFV that activates antiviral autophagy through TRAF6 and MyD88. HCV-encoded NS4B triggers the initiation of autophagy by forming a complex with Rab5 and Vps34. Conversely, HSV-1-encoded ICP34.5 binds with Beclin1; v-GPCR encoded by KSHV negatively regulates autophagy. At later stages of autophagy, viruses utilize DMVs as replication or assembly sites. MHV NSP6 induces autophagy to produce DMVs. These DMVs possess double-membrane-spanning molecular pores, which allows RNAs to be exported to the cytosol. CVB3 exploits autophagy to support its replication in DMVs. Virus blocks the fusion of autophagosomes and lysosomes mainly by targeting the SNARE protein, Rab GTPase family and Tethering factors, or disrupting lysosomal function. CVB3 protease 3C, HPIV3 P protein and EVD viral protease target SNAP29 to inhibit autophagy flux. In addition, CVB3 proteinase 3C targets TFEB for proteolytic processing to disrupt lysosomal function. HCV negatively regulates and positively regulates the maturation of autophagosomes by inducing Rubicon or UVRAG, respectively. KSHV and EBV downregulate RAB7 to block autophagy. SARS-COV-2 ORF3a protein sequestrates and interacts with the HOPS component, and ORF7a reduces the fusion with lysosomes. IAV M2 interacting with Beclin1 may prevent the fusion of autophagosomes and lysosomes. Finally, the virus exploits secretory autophagy to promote viral maturation, egress and cell–cell spreading. DENV takes advantage of autophagy-associated vesicles to promote virus transmission. PV is captured by PS lipid-enriched autophagosome-like vesicles, then vesicles are released from cells. EBV or HCMV recruits autophagy-related protein-coupled membranes to its envelope

At the stage of virus adsorption, autophagy is usually activated through pathogen receptors, such as CD46. After binding with measles virus (MEV), CD46-Cyt-1 (one of the two C-terminal splice variants of CD46) is linked to the VPS34/Beclin1 complex through interaction with the scaffold protein GOPC, which promotes autophagosome formation [55]. Autophagy is also induced when viruses enter cells through endocytosis and the viral envelope fuses with the endosomal membrane to release its own genetic material. Evidence showed that various members of paramyxoviruses and human immunodeficiency virus (HIV) trigger the formation of autophagic spots through membrane fusion, mainly by envelope glycoproteins [56, 57]. The release of genetic material after fusion activates cytoplasmic pattern recognition receptors (PRR) to induce autophagy, which will be described in detail in section “5. autophagy and innate immunity in virus infection”. Subsequently, perturbation of intracellular environment caused by viral replication in the organelle membranes leads to up-regulated autophagy. ER stress and increased ROS induced by HCV replication also trigger autophagy. ER stress is activated through the accumulation of viral proteins, which trigger the unfolded protein response (UPR) to restore homeostasis. Hepatitis C virus (HCV) infection-induced ER-stress inhibits AKT-tuberous sclerosis complex (TSC), then the TSC inhibits the MTOR pathway to induce autophagy [58]. Simultaneously, the UPR signalling pathway is required for promoting the lipidation of LC3 protein and elevation of ROS in response to the HCV infection through the activation of the ATF6 or IRE1 pathways [59]. Moreover, HCV impairs the activation of Nrf2, leading to elevated ROS levels, which up-regulates the phosphorylation level of p62 [60]. Finally, the newly synthesized viral proteins directly or indirectly target autophagy genes to induce the formation of autophagosomes. For example, the HCV-encoded NS4B is capable of initiating autophagy by forming a complex with Rab5 and VPS34 [61]; and human immunity-related GTPase family M (IRGM) protein interacts with HCV NS3 and autophagy genes (ATG5, ATG10, LC3) to promote the lipidation of LC3, thus promoting the formation of autophagosomes [62].

Viral infection suppresses autophagy initiation

Given that autophagy is a part of the antiviral defense mechanism, it is not surprising that viruses evolved mechanisms that allow them to counteract this process. It is mainly achieved by the regulation of viral proteins targeting ATGs, especially for herpesviruses, which are highly adapted to their hosts (Fig. 3).

Herpes simplex virus type 1 (HSV-1)—encoded ICP34.5 was firstly reported to affect autophagy by interacting with Beclin1[63]. Similarly, viral BCL-2 protein and IRS1 and TRS1 encoded by the human cytomegalovirus (HCMV) were also reported to bind with Beclin1, thus impairing the autophagosome formation [64, 65]. A recent study showed that α-herpesvirus Akt-like Ser/Thr kinase limits autophagy in favor of its replication through inhibition of ULK1 and Beclin1 [66]. Subsequently, the v-G protein-coupled receptor (v-GPCR) encoded by Kaposi’s Sarcoma-associated Herpesvirus (KSHV) was reported to negatively regulate autophagy by activating the mTOR pathway; it also mimics the cellular homolog GPCR to down-regulate the ATG14L expression, thus inhibiting autophagy [67, 68]. Therefore, the inhibitory effect of the virus in the initial stage of autophagy can be roughly divided into two categories: the activation of the type I PI3K-AKT-MTOR signalling pathway, or inhibition of the type III PI3K-VPS34-Beclin1 pathway.

Autophagy hijacked by viruses

At a later stage of autophagy, accumulating evidence suggests that different types of viruses have developed their own unique strategies to inhibit, evade, or manipulate the process of autophagy to achieve the goal of survival and propagation (Fig. 3).

Viruses utilize double-membrane vesicles as replication or assembly sites

Coronaviruses (CoV) infection induces autophagy pathway and leads to the formation of DMV for its replication; this comprises viruses such as the mouse hepatitis virus (MHV) [69], Middle East Respiratory Syndrome Coronavirus (MERS-CoV) [70], Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) [71] and SARS-CoV-2 [72, 73]. Nascent viral RNAs were observed in DMVs within cells infected with MERS-CoV, SARS-CoV [70] and gamma-CoV or SARS-CoV-2 [72, 74] by 2D and 3D analysis of viral replication organelles, indicating that DMVs represents the central hub of viral RNA synthesis. Furthermore, a recent authoritative report identified that these DMVs possesses double-membrane-spanning molecular pores, which allows RNA export to the cytosol [75]. MHV NSP6 activates autophagy flux and induces autophagosome formation from ER, while MHV fails to induce DMVs formation in mouse embryonic stem cells lacking ATG5 [76]. The MHV replication levels in mouse embryonic stem cells lacking the ATG5 were significantly reduced compared with cells expressing the ATG5 [77]. This evidence indicates that the replication of coronaviruses is heavily dependent on autophagy-induced DMVs. However, evidence suggested that LC3 protein exists on DMVs and co-localizes with the MHV replication complexes (p22 and N), but other studies demonstrated that non-structural proteins (nsps) from the RNA replication complex do not colocalize with LC3 [78, 79]. This inconsistency may be caused by LC3: a study showed that endogenous LC3 co-localizes with nsps, while exogenously expressed GFP-LC3 does not [80]. In contrast, despite the autophagy seemingly promoting the replication of coronaviruses, it is not necessary in primary murine embryonic fibroblasts (pMEFs) (it can replicate without the ATG7) [80]. Furthermore, non-lipidized LC3-I covers CoV-induced DMVs, implying an autophagy-independent role for nonlipidated LC3-I [80, 81]. Interestingly, the latest research showed that β-CoV hijacks lysosomes rather than the more commonly biosynthetic secretory pathway exploited by other enveloped viruses, for egress, but this process does not seem to be related to autophagy [82]. The strongest evidence is that fractionation by Nycodenz gradients proves that LC3 is not enriched at the MHV genomic RNA containing-fractions in MHV-infected cells; moreover, a similar assay revealed that LC3 and poliovirus (PV) genomic RNA are enriched at the same fractions [82].

Picornaviruses induce DMVs formation to promote its replication, but the origin of DMVs is yet to be identified. PV was the first found to induce the autophagosome membrane rearrangement [83]. Special DMVs with an autophagy-like structure were observed in PV-infected cells [83,84,85]. Blocking the formation of autophagosomes inhibits viral RNA synthesis and subsequent steps of the PV life cycle; however, hindering the acidification of vesicles only inhibits the final stage of viral particles maturation [86]. Virion assembly and maturation of PV may occur in various cellular compartments, so the acidic mature autophagosomes may be used as assembly sites. However, there are also studies showing that PV dsRNA does not co-localize with GFP-LC3, implying that its replication may not occur in autophagosomes [87]. Electron microscopy analysis observed several DMVs in HEK293A and Hela cells infected with coxsackievirus B3 (CVB3) [88], and usurpation of autophagosome supports CVB3 replication [88,89,90]. Nevertheless, autophagy is not absolutely required, Alirezaei et al. reported that the membrane source of DMVs varies and that autophagic membrane may be just one of its origins [91].

Other DMVs derived from cells infected with other viruses such as HCV [92, 93], human norovirus (huNoV) [94] and arterivirus [95] share similar structural characteristics with DMVs originating from a complex ER network. The nsps of these viruses serve critical functions in inducing the DMVs formation. DMVs contain viral nsps, RNA, and enzymatically active replicase in HCV-infected cells. Therefore they are bona fide viral replication organelles sites, but the role of DMVs in the replication of the other two viruses remains to be deciphered.

Virus blocks fusion of autophagosomes with lysosomes

There is evidence that picornaviruses target the SNARE protein complex or disrupt lysosomal function to block autophagy degradation. For instance, CVB3 targets SNAP29 and the adaptor protein PLEKHM1, thus inhibiting autophagy flux by impairing the assembly of the SNARE complex through the catalytic activity of viral protease 3C [96]. In another report, the autophagic flux of CVB3-infected cells was restored by overexpressing another component of the SNARE complex, STX17 [97]. In enterovirus 68 (EV-D68)-infected Hela cells, accumulation of GFP-LC3 spot and cleavaged-SNAP29 by viral protease was simultaneously detected [98]. Transcription factor EB (TFEB), which is targeted for proteolytic processing to disrupt lysosomal function and enhance viral infection, has been identified as a new target of CVB3 proteinase 3C [99]. In addition, a recent study found for the first time that incomplete autophagy can be induced during rhinovirus C (RV-C) infection, but the specific mechanism remains to be studied [100].

Similarly, human parainfluenza virus type 3 (HPIV3) is capable of inducing abnormal accumulation of autophagosomes. The P protein of HPIV3 competitively binds to the SNARE regions of SNAP29, and the binding hinders the interaction of SNAP29 and STX17, thus obstructing the fusion of autophagosomes with lysosomes, and increasing the production of extracellular viral particles [101].

Unlike the aforementioned reports, the fusion of autophagosomes with lysosomes is delayed by the regulation of Rubicon [102], UVRAG [102] and UPR [103,104,105] in different stages of HCV infection. Specifically, at the early stages of HCV infection, NS4B induces Rubicon to inhibit fusion of the autophagosome with lysosomes and promotes the HCV replication; at the late stage of infection, UVRAG is also upregulated and facilitates the maturation of autophagosomes and suppresses HCV replication [102].

Influenza A virus (IAV) infection prevents the late stage of autophagosome maturation. The IAV M2 protein was reported to co-localize with autophagosomes, and plays essential roles in inhibiting the fusion of autophagosomes with lysosomes [106]. Other studies have shown that the interaction between M2 and Beclin1 may prevent the fusion of autophagosomes with lysosomes [28, 106, 107].

The physiological level of autophagy prevents cancer progression by suppressing benign tumour growth, but some oncogenic viruses of the Herpesviridae family induce cancer by dysregulating autophagy, typically exhibiting abnormal accumulation of p62/SQSTM1 [108]. KSHV induces autophagy by replication and transcription activator (RTA), but it downregulates RAB7 to block the final stage of autophagy [109, 110]. Likewise, Epstein-Barr virus (EBV) regulates autophagy through the same strategy to establish stable latent infection [111]. Interestingly, Pringle et al. found that mTORC1 is dispensable for KSHV’s protein synthesis, genome replication, and the release of infectious progeny virions, which means that the virus may have subverted the controlling role of mTOR to autophagy at this stage [112].

Finally, some recent studies showed that SARS-COV-2 possesses a unique strategy to block autophagy. The ORF3a protein sequestrates and interacts with VPS39 to block the fusion of autophagosome/amphisome with lysosomes. Interestingly, ORF3a of SARS-COV does not exert similar capabilities, which may lead to the unique pathogenicity and infectivity of SARS-CoV-2 [113]. Moreover, ORF7a of SARS-CoV-2, another potent autophagy antagonist, reduces the fusion efficiency by down-regulating the acidity of lysosomes [114, 115]. Results from host cells’ network and transcriptome profiling showed that upregulated GSK3B or downregulated SNAP29 may also contribute to mitochondrial and autophagic dysfunctions during the SARS-CoV-2 infection [115, 116].

Secretory autophagy promotes viral maturation, egress and cell–cell spreading

The impact of secretory autophagy on virus maturation, egress, and cell–cell spreading has gained increasing interest in recent years. Flaviviruses, including Zika virus (ZIKV), HCV, and West Nile virus (WNV), and dengue virus (DENV), benefit from the autophagy process, and they are heavily dependent on the availability of the ER membrane during their replication [117,118,119,120,121]. Such reliance provides a theoretical framework for secretory autophagy to promote maturation and release of virus particles and cell–cell spreading. The most robust evidence is that the vesicles secreted by DENV-infected cells contain viral proteins E, prM/M, NS1, and viral RNA, as well as the host LC3-I and lipid droplets [122]. These autophagy-associated vesicles not only allow virus transmission but also avoid antibody neutralisation [122]. Meanwhile, inhibition of autophagy deranges the dengue virion maturation [122, 123]. The latest research also showed that Lyn is critical for virus particles enclosing within membranes to secrete; this process depends on SNARE complexes, ULK1, and Rab GTPases, and occurs with much faster kinetics than the conventional secretory pathway [124]. However, the secretory autophagy hijacked by HCV and ZIKV may cross-talk with the exosomal pathway, but this needs further confirmation [125,126,127,128,129].

Enteroviruses, including PV, CVB3 and rhinovirus, hijack the autophagy pathway to spread effectively in the host by being packaged within the vesicles [130,131,132,133]. Clusters of PV particles are caught by PS lipid enriched autophagosome-like vesicles and released non-lytically from cells. Importantly, it allows multiple viral RNA molecules to be collectively and efficiently transferred into other cells [130]. In the enteric viral infections, these vesicle-cloaked norovirus and rotavirus clusters remain intact during the fecal–oral transmission between individuals, which allows them to be transferred to the next host [134]. Compared with animals ingesting the same amount of free viruses, this mode of transmission leads to more severe clinical symptoms [134]. In addition, Giansanti et al. recently discovered that inhibition of mTORC1 activates TFEB during enterovirus infection, which up-regulates autophagy and lysosomal genes expression, and that TFEB activation promotes the release of virus particles in extracellular vesicles through secretory autophagy [135]. These strategies enable viruses to spread more effectively in or between hosts and evade the direct effect of antiviral drugs to some extent.

Secretory autophagy is also involved in the maturation and release of bunyavirus and herpesviruses. Autophagy is induced under severe fever with thrombocytopenia syndrome virus (SFTSV) infection, and autophagosome serves as SFTSV assembly platform. SFTSV was also observed to egress from autophagic vacuoles[136]. EBV limits lysosomal degradation of viral components for its own benefits as mentioned above. In the subsequent process, EBV was reported to hijack autophagic vesicles as assembly sites and promote the maturation and export of viral particles [111, 137, 138]. Nowag et al. reported that LC3-II is present in purified virus particles as EBV recruits ATG8/LC3-coupled membranes to its envelope [137]. Electron microscopic analysis showed that autophagic vesicles delivered viral particles to the plasma membrane. In addition, some new studies disclosed that autophagy also interferes with genome replication, morphogenesis, and progeny release of HCMV [139,140,141]. Results show that not only LC3-II, but also autophagy receptors such as SQSTM1 exist in the viral envelope [140]. Indeed, SQSTM1 appears to target precipitate tegument proteins or tegument protein complexes before the virion maturation completion [140]. Nevertheless, inhibition of autophagy still enhances replication of HCMV [139, 142, 143]. This indicates that despite autophagy being involved in the assembly of viral particles, it still plays an anti-viral function in the HCMV infection.

Selective autophagy in viral infection

Virus-induced autophagy degradation was firstly recognized as virophagy, which effectively reduces the intracellular load of the virus, but other types of selective autophagy, which exert various effects on viruses, are also triggered (Table 1).

Table 1 Selective autophagy in virus infection

Virophagy

Virophagy, also called xenophagy, is an important antiviral defense mechanism that not only targets the virus or viral protein for degradation but also promotes the host’s immune responses, such as inflammation regulation, antigen recognition and presentation. However, the molecular mechanism of autophagy recognizing whole virus particles or viral components and targeting them to autophagosomes has not been sufficiently investigated.

In the model organisms, Drosophila and Caenorhabditis elegans, virophagy is considered to be an inherent antiviral program [144, 145]. The lack of adaptive immune interference in these organisms provides unique conditions for studying the contribution of autophagy to innate immunity, especially epithelial defense. For instance, mutations in the autophagy genes, ATG18/WIPI2, ATG1/ULK1, ATG5, and ATG8A/LC3, in D. melanogaster S2 cells increase the susceptibility of Drosophila to vesicular stomatitis virus (VSV) [146]. Another study showed that during the Rift Valley Fever Virus (RVFV) infection, TLR7-mediated activation of autophagy limits RVFV replication and reduces mortality, while a knock-down of key autophagy components in C. elegans (e.g. ATG8/LGG-1 and SQSTM1/SQST-1) increased the load of the virus [147]. Correspondingly, autophagy is activated through starvation or through the autophagy negative regulator MTOR/LET-363, which reduces the pathogen load of Orsay virus [148]. These findings may provide evidence that the original function of autophagy is to eliminate and degrade harmful microorganisms that manage to enter the cytoplasm. However, it is surprising that in higher eukaryotes, the function of autophagy is gradually hijacked by viruses, which may be the result of the co-evolution between viruses and eukaryotes.

In other regards, virophagy prevents tissue injury and host cellular death by inhibiting the inflammatory cytokines production and intracellular microbes removal. Previous studies have shown that the capsid protein of Sindbis virus (SINV) is degraded through P62, and that ATG5 disruption in SINV-infected neurons decreases viral proteins clearance, and also results in the accumulation of cellular p62 and increased cell death [149]. In the same way, galectin-9 restricts hepatitis B virus (HBV) replication via p62-mediated selective autophagy of viral core proteins [150]. Genetic deletion of the Fanconi anemia (FA) pathway genes with DNA damage repair function blocks the virophagy and heightens susceptibility to lethal viral encephalitis during the SINV and HSV-1 infection [151].

The importance of non-canonical forms of virophagy in the host antiviral immune process has recently received extensive scientific attention. It was reported that the WD40 domain of ATG16L1 plays a critical role in the LC3 lipidation on single membranes during non-canonical autophagy [152]. Mice lacking the WD40 domain are extraordinarily sensitive to the low-pathogenicity IAV, and they suffer serious inflammatory pathological damage in the lungs; this is due to the non-canonical autophagy slowing the fusion of IAV envelopes with endosomes and down-regulating the IFN responsive genes [153]. In addition, non-canonical autophagy also facilitates the presentation of major histocompatibility complex class II (MHC II) antigens in IAV-infected mouse dendritic cells (DCs) [152]. When the autophagy levels are reduced, the beneficial enteric virus becomes pathogenic. It is probably because ATG16L1 in the epithelium prevents exacerbated TNFα, IFNγ and commensal bacteria-dependent intestinal injury after murine norovirus (MNV) infection [154]. In another study, massive amounts of lipidated LC3 were observed in ATG5, ATG7, or BECN1-silenced hepatocytes infected with Crimean Congo hemorrhagic fever virus (CCHFV). This implies the occurrence of non-canonical autophagy, but this accumulated lipidated LC3 seems to have no effect on virus replication [155]. Remarkably, a new alternative lipidation mechanism of ATG8-PS in the lysosomal compartment in the process of non-canonical autophagy was discovered recently; being different from the canonical conjugation of ATG8 protein to PE, ATG8-PS conjugation is a unique “molecular signature” for the non-canonical autophagy [156]. It has been confirmed that the influenza virus induces the non-canonical ATG8-PS autophagy, but it is still not clear how this unique modification affects virus replication [156].

Mitophagy

Mitophagy is a vital form of autophagy that specifically degrades dysfunctional or redundant mitochondria. Since the accumulation of dysfunctional mitochondria induces a series of immune responses, mitophagy limits the secretion of inflammatory cytokines and directly regulates the presentation of mitochondrial antigens and immune cell homeostasis [157]. It is known that promoting mitophagy inhibits the secretion of type I IFN, which depends on the increased ROS production and mitochondrial retention [158, 159]. Inhibition of mitophagy activates Nod-like receptor protein 3 (NLRP3) inflammasome to further increase the secretion of IL-1β/IL-18 and the expression of NF-Κb [160]. Therefore, mitophagy is likely to be usurped by viruses for suppression of antiviral immunity, or be inhibited to cause mitochondrial degradation dysfunction, resulting in a strong immune response and severe damage to the host. HIV [161,162,163], herpesviruses [164], influenza viruses [165, 166], EBV [167], HPIV3 [168], senecavirus A [169] and SARS-CoV-2 [170,171,172] all appear to possess this ability.

Considering influenza viruses as an example: NOD2 Receptor interacting protein kinase 2 (Ripk2)−/− cells exhibit accumulation of damaged mitochondria, but Ripk2−/− cells are susceptible to IAV. After infection, IAV activates the NLRP3 and increases the levels of IL-18 and IL-1β. Therefore, NOD-RIPK2 signal transduction protects against virally triggered immunopathology by negatively regulating NLRP3 through mitophagy [173]. Our study confirmed that the IAV M2 protein increases the formation of ROS-dependent mitochondrial antiviral signalling protein (MAVS) aggregates [174]. It antagonizes autophagy and competes with ATG5 and LC3B to bind to MAVS, which reduces the formation of LC3B-MAVS and ATG5-MAVS complexes, as well as degradation of MAVS aggregates; followed by elevating the MAVS-mediated innate immune response [174]. Furthermore, the high molecular weight aggregates of the IAV virulence protein, PB1-F2, can be transferred to the inner membrane of mitochondria through the TOMM40 channel. This process reduces the membrane potential and promotes the fragmentation of mitochondria, which in turn promotes the activation of NLRP3 [175,176,177,178]. On the other hand, PB1-F2 protein acts as an autophagy receptor and mediates the induction of complete mitochondrial autophagy by simultaneously interacting with LC3B and the mitochondrial protein, the Tu elongation factor, mitochondrial (TUFM). This interaction increases MAVS degradation and weakens the production of type I IFN [165, 179]. A recent investigation showed that the PB1 protein of IAV also suppresses the innate immune response by targeting MAVS for NBR1-mediated selective autophagic degradation [180].

ER-phagy or reticulophagy

The ER is a highly dynamic network that has a central role in cell metabolism and cellular organization. ER‐phagy contributes to the remodelling of the network under fluctuating conditions to ensure continuous normal functioning of ER and minimize stress [181]. As mentioned earlier, ER is the main membrane source of DMVs and viral replication or assembly site for viruses such as flaviviruses, CoVs and picornaviruses. Therefore, ER-phagy exerts innate antiviral functions against this group of viruses.

FAM134B is an important ER-phagy receptor, as its absence helps ER expansion and leads to ER stress. Various lines of evidence suggested that the replication of flavivirus and ebola virus (EBOV) are both limited by the FAM134B-dependent ER-phagy [182, 183]. However, flavivirus NS3-encoded protease and NS3 cofactor NS2B can cleave FAM134B to largely avoid this limitation [182]. Consistent with the above report, depletion of BPIFB3 improves the FAM134B ER-phagy and impairs the replication of flavivirus [184]. Another the ER-phagy receptor, RTN3, has been implicated in the remodelling of ER tubules in response to pathogen infections [185]. Flavivirus targeting RTN3.1A hijacks the ER-phagy by the NS4A protein of WNV to remodel the host membrane and stabilize the viral protein in the ER, but RTN3 interacts with NS4B of the HCV to abolish the NS4B self-interaction, thus negatively regulating viral replication [186, 187].

Lipophagy

Autophagy also regulates lipid metabolism by modifying lipid droplets (LDs), a process termed lipophagy [188, 189]. LDs are composed of a neutral lipid core and surrounded by a monolayer of phospholipids. There are several proteins on the surface of LDs, which are used to supply energy when required by cells [190].

DENV induces autophagy to regulate lipid metabolism, which requires components of the autophagocytic machinery to achieve robust replication [191, 192]. During DENV or ZIKV infection, lipophagy is activated and stored triglycerides are depleted, which increases the release of β-oxidized fatty acids in mitochondria, thereby releasing the energy required for virus replication and assembly. The LDs then became a hotbed for viral replication [192,193,194]. Adding exogenous free fatty acids to autophagy-deficient cells restores the DENV replication. Furthermore, the application of Etomoxir, which blocks the transport of fatty acids to the mitochondria, blocks this process [191].

Aggrephagy

Newly synthesized proteins need to be folded properly, but it is frequently hindered by oxidative stress, transcriptional/translational errors or mutations that cause protein misfolding [195]. Misfolded proteins form aggregates, which are then removed by aggrephagy. In the past, aggrephagy disorder was believed to be involved in the onset of many neurodegenerative diseases [196], it has been discovered that herpesviruses infections induce aggrephagy, which is a typical example of a conserved immune system evasion mechanism [197].

According to the latest reports, murine cytomegalovirus (MCMV) M45 protein motivates the aggregation and subsequent degradation of the receptor-interacting protein kinase 1 (RIPK1) and the NF-κB essential modulator (NEMO) [197]. The aggregation of RIPK1 and NEMO blocks antiviral responses such as the induction of necroptosis and the activation of NF-κB, and in that way contributes to the immune evasion of virus and cell viability. M45 requires an “induced protein aggregation motif (IPAM)” to induce the target proteins aggregation, then M45 recruits the LC3-interacting adaptor protein, TBC1D5 and VPS26B, facilitating degradation of aggregates [197]. Of note, some herpesviruses encode M45-homologous proteins containing the IPAM, such as EBV BORF2, HSV-1 ICP6, HSV-2 ICP10 and HHV-8 ORF61. Experimental results show that HSV-1 ICP6 has comparable activity to M45 [197].

Ferritinophagy

Ferritinophagy is a special form of autophagy that specifically targets iron-sequestering protein ferritin for maintaining cellular iron homeostasis [189]. Although iron is an important part of various enzymes and proteins, excess free iron induces oxidative stress and the formation of ROS, which accelerates the cell death [198]. Ferritinophagy is regulated by the nuclear receptor coactivator 4 (NCOA4), which binds ferritin and marks it as autophagic cargo for iron recycling under low iron conditions [199]. At the same time, the replication of various viruses is affected by the iron concentration; these comprise HCV [200], HSV-1 [201], bovine viral diarrhea virus (BVDV) [201], HIV-1 [202], WNV [203], HCMV [204] and HPIV2 [205].

In some studies, inhibition of ferritinophagy has been recognised as a potential mechanism of prevention of cell death during viral infection. For example, the pUL38 protein of HCMV binds to USP24 to antagonize the cellular stress response, thereby preventing premature cell death [204]. During the HCMV infection, protein levels of NCOA4 and ferritinophagy are regulated, and Tiron and iron chelators ciclopirox olamine specifically protect cells from pUL38-deficient HCMV infection-induced cell death [204]. This shows that pUL38 antagonizes USP24 to reduce ferritinophagy and increase cell viability and successful virus infection. Similarly, the V-2 protein of HPIV2 weakens ferritinophagy by interfering with the interaction between the ferritin heavy chain 1 (FTH1) and NCOA4, allowing infected cells to avoid apoptotic cell death and facilitating effective viral replication of HPIV2 [205].

Autophagy and the innate immunity in viral infections

Antiviral interferon responses, inflammation and autophagy

The viral invasion will trigger the activation of some specific PRRs, including: 1) Toll-like receptors (TLRs), such as TLR3 (dsRNA), TLR7 and TLR8 (ssRNA), and TLR9 (DNA with unmethylated CpG sites); 2) RIG-I like receptors (RLRs) (viral RNAs); and 3) Nod-like receptors (NLRs) [206]. Moreover, the cytosolic DNA sensor, cyclic GMP–AMP (cGAMP) synthase (cGAS), recognizes dsDNA during the DNA virus infection [206]. TLR7, TLR8 and TLR9 recruit the adaptor protein, myeloid differentiation primary response 88 (MYD88), while TLR3 recruits another type of adaptor, TIR-domain-containing adapter-inducing interferon-β (TRIF). Both adaptors activate NF-κB to synthesize inflammatory factors or the interferon pathway to induce IFN production in plasmacytoid pDC [207, 208]. MYD88 also recruits interleukin 1 receptor-associated kinase (IRAK) 1 and IRAK4 [209]. IRAK1 is phosphorylated to recruit E3 ubiquitin ligase and the scaffold protein, TNF receptor-associated factor 6 (TRAF6) [209]. Ubiquitinated TRAF6 induces the phosphorylation of the inhibitor of the IκB kinase (IKK) complex, activating the NF-κB [210]. Cytosolic viral DNA triggers STING1 through binding to cGAMP, resulting in the production of type I IFNs [211]. STING1 upregulates the expression of NF-κB-dependent pro-inflammatory cytokines [212]. Nevertheless, ATG9a inhibits the STING1 aggregation on Golgi apparatus-derived compartments to regulate the innate immune response; AMPK and ULK1 mediate the phosphorylation of STING1, which leads to the degradation of STING1, thereby limiting cytokine levels [213]. The RIG-I-MAVS-TRAF6 signal transduction axis is required for the RIG-I-mediated autophagy. After activation of RIG-I, Beclin1 translocates to mitochondria and then interacts with TRAF6 [214]. MAVS binds to TRAF2, TRAF3, TRAF5, or TRAF6 through its PRR domain, which promotes the activation of the TBK1 complex [215, 216]. The TBK1 complex promotes homodimerization and phosphorylation of interferon regulatory factors (IRFs) to activate IRFs, which then transfer to the nucleus where they link to IFN-stimulated response elements and motivate the transcription of target genes [216]. Moreover, TLR signal transduction enhances the interaction between TRIF or MyD88 and Beclin1, and reduces the binding of Beclin1 to BCL-2, which ultimately activates autophagy [217]. In contrast, tripartite motif-containing protein 32 (TRIM32) targets TRIF to negatively regulate TLR3-mediated immune responses for degradation of TAX1BP1-mediated selective autophagy [218]. Mitochondria exert antiviral functions through MAVS. After RIG-I recognizes the RNA produced by a viral infection and replication, it recruits MAVS to locate on the mitochondria and triggers MAVS activation. MAVS activation further activates IRFs and NF-κB, leading to the expression of IFN and pro-inflammatory cytokines [219]. The ATG5-ATG12 complex affects the formation and stability of MAVS aggregates by directly binding to the Caspase recruitment domain (CARD) of MAVS and RIG-I, thereby negatively regulating the signal transduction of the RLRs pathway [175, 220]. However, the absence of autophagy results in ROS-dependent signal transmission of RLRs [159]. Therefore, autophagy may be used as a negative feedback mechanism to regulate the type I IFN response. In parallel, autophagy removes mitochondria, leading to a reduced release of mitochondrial-derived damage-associated molecular patterns (DAMPs) and suppression of the NLRP3 inflammasome activation [221]. Rubicon is a protein that interacts with the Beclin1-VPS34 complex that inhibits the activity of CARD9, BCL10, and MALT1 (CBM complex) by binding to CARD9, thereby terminating RIG-I- or MDA5-mediated pro-inflammatory signal transduction [222] (Fig. 4).

Fig. 4
figure 4

Autophagy and the innate immune in viral infection. The genetic material of RNA or DNA viruses is recognized by PRRs or cGAS, which facilitate viral induction of antiviral autophagy to improve the IFN production, thereby limiting virus replication. Specifically, VSV and RVFV activate antiviral autophagy and increase the production of type I IFNs through TLR-7 and MYD88 signal transduction; while LRV achieves it through TLR3 and TRIF, which triggers the degradation of NLRP3; HSV activates autophagy and induces interferon production through TLR9. STING-dependent autophagy induced by inflammation limits ZIKV infection. IAV M2 protein increases the formation of MAVS aggregates. It antagonizes autophagy through reducing the formation of ATG5-MAVS and LC3B-MAVS complexes, thereby enhancing the innate immune response. Conversely, HCV inhibits the innate immune response by inducing the autophagic degradation of TRAF6. During the HPV-1 infection, the interaction between cGAS and Beclin1 not only halts the production of IFN by inhibiting the synthesis of cGAMP, but also prevents excessive activation of cGAS to sustain systematic immune balance by enhancing autophagy degradation of viral DNAs. APCs initiate adaptive immunity by presenting protein fragments through MHC. M1 protein of Influenza is targeted by LC3 to autophagosomes, which fuse with MIIC to enhance the antigen presentation of CD4+ T cells. LC3 combined with HIV/SIV gag antigen targeted to autophagosomes enhance the HIV-specific CD4+ T cell response. HIV-1 envelope and ICP34.5 of HSV1 inhibit autophagy in DCs, escaping MHC-restricted presentation of its antigens. ORF8 of SARS-CoV-2 directly interacts with MHC Ι and mediates its down-regulation through autophagy to evade immune surveillance. HSV-1 infection induces autophagy and increases the presentation of peptides derived from HSV-1 glycoprotein B to CD8+ T cells in a manner that requires proteasome function and secretion pathways. Similarly, pUL138 of HCMV is presented by autophagy in a TAP-independent manner that involves MHC I loading in endosomal compartments

Consequently, the relationship between autophagy and the immune response during viral infection is highly complicated and must be specifically analyzed according to different viral infections. Due to almost all viral infections inducing a complex immune response, below we provide descriptions of some representative viruses.

Specifically, autophagy-deficient ATG5 pDCs decrease TLR7-dependent IFNs production during the VSV and Sendai virus (SeV) infection [223]. Moreover, TLR-7 and MyD88 signal transduction hinders the RVFV replication in Drosophila and mammals by activating the antiviral autophagy [147]. Leishmania RNA virus (LRV) induces type I IFN production by activating TLR3 and TRIF, which triggers the ATG5-mediated autophagy-induced degradation of NLRP3 inflammasome in macrophages [224]. ATG5 also facilitates the production of TLR9-induced IFN-I in pDCs infected with HSV-1 [225]. STING1 is essential for an RNA-virus triggered autophagy, foot-and-mouth disease virus (FMDV)-induced integrated stress response originates from RIG-I, which transmits signals to STING1 and leads to degradation of STING1 itself [226]. In addition, STING-dependent autophagy induced by inflammation has been shown to limit ZIKV infection in the Drosophila brain [227, 228] (Fig. 4).

Conversely, HCV inhibits the host's innate immune response by inducing the autophagic degradation of TRAF6 [229]. Srikanta et al. found that HCV replication induces chronic ER stress in persistently infected cells and an autophagic response that selectively impaired the type I IFN signalling [230]. During HPV-1 infection, the interaction between cGAS and Beclin1 not only halts the production of IFN by inhibiting the synthesis of cGAMP, but also prevents excessive activation of cGAS to sustain systematic immune balance by enhancing autophagy-mediated degradation of cytosolic viral DNAs [231]. As mentioned in the Mitophagy part, the virus controls the RIG-I/MAVS-mediated production of IFN-I and activation of inflammasomes by promoting mitochondrial autophagy, which will not be reiterated. OTUD7B/Cezanne (OTU deubiquitinase 7B) acts as a negative regulator of antiviral immunity by deubiquitinates SQSTM1/p62 and promotes IRF3 degradation [232]. In addition, a newly discovered selective autophagy receptor CCDC50 targets RIG-I/MDA5 and degrades them after infection with VSV, SEV, and EMCV, thereby inhibiting IRF3/7 activation and NF-κB-mediated inflammation to enhance virus replication [41] (Fig. 4).

Collectively, the interaction between autophagy and the immune response is a double-edged sword in viral infection. On one hand, the activation of TLRs, RLRs, or cGAS-STING by viral infection may help to induce autophagy to improve the IFN production, thereby limiting virus replication; on the other hand, autophagy degrades damaged organelles and immune signal transduction proteins to impair the immune response process, or in extreme cases, prevent excessive immune responses to maintain the homeostasis of the intracellular environment, thereby, thus eventually promoting replication of the virus.

Autophagy and viral antigen presentation

Autophagy proteins are also involved in different aspects of antigen presentation. Antigen-presenting cells (APCs) are capable of initiating adaptive immune response by presenting protein fragments through MHC molecules. MHC class I (MHC I) is expressed in nucleated cell types. Intracellular antigens are processed by the proteasome and transported to the ER through the transporter associated with TAP, which then binds to MHC I, and is typically presented to CD8+ T cells [233]. MHC II and related molecules are expressed by APCs or by other cells after being stimulated by IFN-γ. MHC II molecules mainly load extracellular antigens in the late endosomal MHC II inclusion compartment (MIIC), and also load a part of endogenous antigens via a variety of intracellular pathways [234, 235], which are presented to CD4+ T cells [233, 236]. It is important to note that an extra mechanism of loading exogenous antigens onto MHC I molecules occurs through a process called cross-presentation [237]. After autophagosome cargo is degraded by lysosomes, the antigen can be presented via the MHC II and promote the activation of CD4+ T cells [238]. In addition, autophagy mediates the internalization and degradation of MHC I molecules to limit the presentation of antigen [208]. In DCs deficient with autophagy-related genes, VPS34, ATG5, or ATG7, the surface expression of MHC I and induction of CD8+ T cell activation is increased [239, 240]. Recent research also showed that MHC I is targeted for degradation by the autophagy pathway involving the selective autophagy receptor NBR1 [241]. In contrast, some studies have provided evidence that autophagy enhances the MHC I antigen presentation [242]. For example, HeLa cells treated with the selective PI3K inhibitor, 3-methyladenine, display reduced autophagy-mediated degradation of defective ribosomal products (DRiPs), which is also accompanied by enhanced proteasome degradation and class I antigen presentation [238, 243] (Fig. 4).

Early studies found that influenza matrix protein 1 (M1) is targeted by ATG8/LC3 to autophagosomes, and then autophagosomes continuously fuse with MIIC to enhance the antigen presentation to CD4+ cells clones [244]. Interestingly, proteasome-dependent endogenous antigen processing, but not autophagy, contributes to the global influenza CD4 ( +) response [245]. In addition, the DCs lacking ATG16L1 WD 40 CTD infected with IAV exhibited a reduced MHC II antigen presentation. It suggests that non-canonical autophagy may complement the MHC II antigen presentation process [152]. Research on HIV showed the LC3 fusion protein combined with HIV/SIV gag antigen targeted to autophagosomes can effectively enhance the HIV-specific CD4 ( +) T cell response [246]. Nevertheless, HIV-1 envelope and ICP34.5 of HSV1 inhibit autophagy in DC and escape MHC-restricted presentation of its antigens [247] (Fig. 4).

The effect of autophagy on MHC I antigen presentation appears to be paradoxical, as there are differences in MCH I antigen presentation induced by specific viral infections. During the IAV and lymphocytic choriomeningitis virus (LCMV) infection, a lack of ATG5 leads to an enhanced virus-specific CD8+ T cell response [239]. DCs lacking VPS34 display enhanced presentation of chicken ovalbumin (OVA), IAV, and LCMV antigens to CD8+ T cells [240]. Remarkably, a recent study confirmed that an open reading frame 8 (ORF8) of SARS-CoV-2 directly interacts with MHC Ι and mediates its down-regulation through Beclin1–mediated selective autophagy to evade immune surveillance [248]. However, after HSV-1 infects macrophages to induce autophagy, it increases the presentation of a peptide derived from the HSV-1 glycoprotein B to CD8+ T cells in a manner that requires proteasome function and secretion pathways [249]. Similarly, an HCMV-encoded antigen of the type I integral membrane protein, pUL138, can be presented by autophagy in a TAP-independent manner that involves MHC I loading in endosomal compartments [242] (Fig. 4).

In conclusion, autophagosomes induced by viral infection carry viral components and fuse with MIIC to provide proteins for MHC II presentation to CD4+ cells to induce an antiviral immune response, but some viruses escape this immune process by reducing autophagy. Viral proteins and autophagy proteins mediate the direct degradation of MHC I, and autophagy deficiency leads to a virus-specific CD8+ T cell response enhancement. However, it seems that autophagy does not affect other ways of MHC I antigen presentation, which requires further in-depth research.

Virus-specific induction of autophagy

Recently, Dr. Beth Levine’s laboratory utilized genome-wide siRNA screening to discover a type of virus-induced autophagy mediated by sorting nexin 5 (SNX5), which has subsequently attracted widespread attention [250]. Virus-induced autophagy differs from the general autophagy mediated by starvation or mTOR, and the non-canonical forms of autophagy induced by bacteria or osmotic stress. Both SNX5-deficient cells and SNX5-knockout mice are more susceptible to SIN, HSV-1, WNV, CHIKV, and other viruses, but there is no difference in the susceptibility to recombinant viruses that have the ability to inhibit autophagy [250]. When the virus enters the endosome, SNX5 increases the curvature of the membrane through the BAR domain to activate the autophagy-related PI3KC3-C1 kinase complex, and generates the key autophagy initiation signal, PI (3) P, on the endosome membrane, thus activating the autophagy [250]. However, the mechanism by which luminal viruses stimulate the SNX5-PI3KC3 axis on the cytoplasmic surface of endosomes is still unidentified. These findings confirm the existence of SNX5-mediated activation of the viral autophagy signalling pathway, which represents a novel and important host defense mechanism.

Indeed, the comparative characterization of the SINV proteome from mammalian and invertebrate hosts identified SNX5 as an important host factor for alphavirus replication [251]. Asuka et al. have previously reported co-localization of fluorescently-labeled EBOV particles with SNX5 in the process of researching the internalization mechanism of EBOV [252]. In addition, SNX5 and PI (3) P play a key role in the formation of the viral replicase complexes (VRCs) bound on the organelle membrane of the tomato bushy stunt virus (TBSV) [253]. Importantly, HCMV-encoded UL35 binds to and negatively regulates SNX5, thereby regulating cellular transport pathways that affect the virus assembly process [254]. These results indicate that the endosomal membrane remodelling process affects the entry, replication, and assembly processes of many viruses. The regulatory relationships among SNX5, various viruses and autophagy require further research.

Conclusion

As a ubiquitous metabolic pathway in most multicellular organisms, autophagy exhibits strong defense capabilities against viral invasion, including the regulation of inflammation, promotion of antigen presentation, and the degradation of viral components or particles. Nevertheless, the diversity of methods exploited by different viruses to manipulate the autophagy pathway is equally impressive. Viruses can use the autophagy pathway to interfere with the immune response or prevent cell death, and to take advantage of autophagy-related metabolites. Some viruses can even directly exploit autophagosomes for assembly, or use secretory autophagy to promote the egress of virus particles and cell–cell spreading, and avoid antibody neutralization. However, whether autophagy contributes to or inhibits viral replication is indeterminate and dependent on several factors, including types of infected cells, the virus strains, and conditions of infection. Another key point that should not be ignored is that most of experimental designs investigating virus role in autophagy are carried out in cancer cell lines, given that autophagy plays a great regulatory role in cancer cell survival mechanisms, the effect of autophagy on virus replication may require in vivo experiments to be more convincing. In addition, viruses that cannot be assembled inside the cell (e.g. HPIV3, IAV and other viruses), can induce the accumulation of autophagosomes, and hinder the membrane fusion between autophagosomes and lysosomes. The specific role of these accumulated autophagosomes requires further research. Importantly, some new discoveries, such as the influence of ATG8-PS alternative lipidation mechanism on virus replication in viruses-triggered non-classical autophagy and mechanisms by which viruses specifically induce autophagy, offer novel directions for future research. This review provides an important foundation for the development of broad-spectrum antiviral treatment strategies and drugs based on the regulation of autophagy.

Availability of data and materials

All data relevant to this review are included in the text, references, table, and figures.

Abbreviations

APC:

Antigen-presenting cell

ATG:

Autophagy-related

Bcl-2:

B cell lymphoma-2

BVDV:

Bovine viral diarrhea virus

CARD:

Caspase recruitment domain

CCHFV:

Crimean-Congo hemorrhagic fever virus

CHIKV:

Chikungunya virus

CoV:

Coronavirus

CVB3:

Coxsackievirus B3

CVB4:

Coxsackievirus B4

DENV:

Dengue virus

DMV:

Double membranous vesicle

EBOV:

Ebolavirus

EBV:

Epstein-Barr virus

EMCV:

Encephalomyocarditis virus

ER:

Endoplasmic reticulum

ESCRT:

Endosomal sorting complex required for transport

EV71:

Enterovirus 71

EV-D68:

Enterovirus 68

FMDV:

Foot-and-mouth disease virus

HCMV:

Human Cytomegalovirus

HCoV-NL63:

Human Coronavirus NL63

HCV:

Hepatitis C virus

HIV:

Human immunodeficiency virus

HPIV3:

Human parainfluenza virus type 3

HRV:

Human rhinovirus

HSV-1:

Herpes simplex virus types 1

IAV:

Influenza A virus

IFN:

Interferon

IM:

Isolation membrane

IRAK:

Interleukin 1 receptor associated kinase

IRF:

Interferon regulatory factors

IRF:

Interferon regulatory factors

K63:

Lys63

KSHV:

Kaposi’s sarcoma-associated herpesvirus

LC3:

Ligase of microtubule-associated protein L chain 3

LCMV:

Lymphocytic choriomeningitis virus

LD:

Lipid droplets

LRV:

Leishmania RNA virus

MAVS:

Mitochondrial antiviral signaling protein

MCMV:

Murid herpesvirus 1

MERS-CoV:

Middle East Respiratory Syndrome Coronavirus

MHC:

Major histocompatibility complex

MHV:

Mouse Hepatitis Virus

MVB:

Multivesicular bodies

MyD88:

Myeloiddifferentiationfactor88

NF-κB:

Nuclear factor-κB

NLRP3:

Nod-like receptor protein 3

PAMPs:

Pathogen-associated molecular patterns

PI (3) P:

Phosphatidylinositol 3-phosphate

PRRs:

Pattern-recognition receptors

PV:

Poliovirus

RIG-I:

Retinoic acid-inducible gene I

RLR:

RIG-I-like receptor

ROS:

Reactive oxygen species

RVFV:

Rift Valley Fever Virus

SARS-CoV:

Severe Acute Respiratory Syndrome Coronavirus

SINV:

Sindbis virus

SNARE:

Soluble N-ethylmaleimide-sensitive factor attachment protein receptor

TAP:

Transporter associated with antigen processing

TAX1BP1:

TAX1-binding protein 1

TBK1:

TANK binding kinase 1

TBSV:

Tomato bushy stunt virus

TLRs:

Toll-like receptors

TRAF:

TNF receptor associated factor

TRIF:

TIR domain-containing adaptor molecule 1

TRIM32:

Motif-containing protein 32

VSV:

Vesicular stomatitis virus

WNV:

West Nile virus

ZIKV:

Zika virus

CMA:

Chaperone-mediated autophagy

ERGIC:

ER-Golgi intermediate compartment

FTH1:

Ferritin heavy chain 1

IRGM:

Immunity-associated GTPase family M

LAP:

LC3‐associated phagocytosis

MTOR:

Mechanistic target of rapamycin

NBR1:

Neighbor of BRCA1 gene

NCOA4:

Nuclear receptor coactivator 4

PS:

Phosphatidylserine

RTA:

Replication and transcriptional activator

SFTSV:

Severe fever with thrombocytopenia syndrome virus

SNX5:

Sorting nexin 5

TGN:

Trans-Golgi network

TSC:

Tuberous sclerosis complex

v-GPCR:

V-G protein-coupled receptor

References

  1. Doria A, Gatto M, Punzi L. Autophagy in Human Health and Disease. N Engl J Med. 2013. https://doi.org/10.1056/NEJMc1303158.

    Article  Google Scholar 

  2. Walker PJ, Siddell SG, Lefkowitz EJ, Mushegian AR, Dempsey DM, Dutilh BE, et al. Changes to virus taxonomy and the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses (2019). Arch Virol. 2019. https://doi.org/10.1007/s00705-019-04306-w.

    Article  Google Scholar 

  3. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature. 2011. https://doi.org/10.1038/nature09782.

    Article  Google Scholar 

  4. Shibutani ST, Yoshimori T. A current perspective of autophagosome biogenesis. Cell Res. 2014. https://doi.org/10.1038/cr.2013.159.

    Article  Google Scholar 

  5. Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell. 2009. https://doi.org/10.1091/mbc.E08-12-1249.

    Article  Google Scholar 

  6. Yue Z, Zhong Y. From a global view to focused examination: understanding cellular function of lipid kinase VPS34-Beclin 1 complex in autophagy. J Mol Cell Biol. 2010. https://doi.org/10.1093/jmcb/mjq028.

    Article  Google Scholar 

  7. Axe EL, Walker SA, Manifava M, Chandra P, Roderick HL, Habermann A, et al. Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum. J Cell Biol. 2008. https://doi.org/10.1083/jcb.200803137.

    Article  Google Scholar 

  8. Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol. 2009. https://doi.org/10.1038/nrm2708.

    Article  Google Scholar 

  9. Xie Z, Nair U, Klionsky DJ. Atg8 controls phagophore expansion during autophagosome formation. Mol Biol Cell. 2008. https://doi.org/10.1091/mbc.E07-12-1292.

    Article  Google Scholar 

  10. Suzuki H, Osawa T, Fujioka Y, Noda NN. Structural biology of the core autophagy machinery. Curr Opin Struct Biol. 2017. https://doi.org/10.1016/j.sbi.2016.09.010.

    Article  Google Scholar 

  11. Fader CM, Sanchez DG, Mestre MB, Colombo MI. TI-VAMP/VAMP7 and VAMP3/cellubrevin: two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways. Biochim Biophys Acta. 2009. https://doi.org/10.1016/j.bbamcr.2009.09.011.

    Article  Google Scholar 

  12. Furuta N, Fujita N, Noda T, Yoshimori T, Amano A. Combinational soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins VAMP8 and Vti1b mediate fusion of antimicrobial and canonical autophagosomes with lysosomes. Mol Biol Cell. 2010. https://doi.org/10.1091/mbc.E09-08-0693.

    Article  Google Scholar 

  13. Itakura E, Kishi-Itakura C, Mizushima N. The Hairpin-type Tail-Anchored SNARE Syntaxin 17 Targets to Autophagosomes for Fusion with Endosomes/Lysosomes. Cell. 2012. https://doi.org/10.1016/j.cell.2012.11.001.

    Article  Google Scholar 

  14. Wang Y, Li L, Hou C, Lai Y, Long J, Liu J, et al. SNARE-mediated membrane fusion in autophagy. Semin Cell Dev Biol. 2016. https://doi.org/10.1016/j.semcdb.2016.07.009.

    Article  Google Scholar 

  15. Shen QH, Shi Y, Liu JQ, Su H, Huang JT, Zhang Y, et al. Acetylation of STX17 (syntaxin 17) controls autophagosome maturation. Autophagy. 2021. https://doi.org/10.1080/15548627.2020.1752471.

    Article  Google Scholar 

  16. Fader CM, Sanchez D, Furlan M, Colombo MI. Induction of autophagy promotes fusion of multivesicular bodies with autophagic vacuoles in k562 cells. Traffic. 2008. https://doi.org/10.1111/j.1600-0854.2007.00677.x.

    Article  Google Scholar 

  17. Munafo DB, Colombo MI. Induction of autophagy causes dramatic changes in the subcellular distribution of GFP-Rab24. Traffic. 2002. https://doi.org/10.1034/j.1600-0854.2002.30704.x.

    Article  Google Scholar 

  18. Nozawa T, Aikawa C, Goda A, Maruyama F, Hamada S, Nakagawa I. The small GTPases Rab9A and Rab23 function at distinct steps in autophagy during Group A Streptococcus infection. Cell Microbiol. 2012. https://doi.org/10.1111/j.1462-5822.2012.01792.x.

    Article  Google Scholar 

  19. Ao X, Zou L, Wu Y. Regulation of autophagy by the Rab GTPase network. Cell Death Differ. 2014. https://doi.org/10.1038/cdd.2013.187.

    Article  Google Scholar 

  20. Wong YC, Ysselstein D, Krainc D. Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature. 2018. https://doi.org/10.1038/nature25486.

    Article  Google Scholar 

  21. Diao J, Liu R, Rong Y, Zhao M, Zhang J, Lai Y, et al. ATG14 promotes membrane tethering and fusion of autophagosomes to endolysosomes. Nature. 2015. https://doi.org/10.1038/nature14147.

    Article  Google Scholar 

  22. Yu L, Chen Y, Tooze SA. Autophagy pathway: Cellular and molecular mechanisms. Autophagy. 2018. https://doi.org/10.1080/15548627.2017.1378838.

    Article  Google Scholar 

  23. Matsui T, Jiang PD, Nakano S, Sakamaki Y, Yamamoto H, Mizushima N. Autophagosomal YKT6 is required for fusion with lysosomes independently of syntaxin 17. J Cell Biol. 2018. https://doi.org/10.1083/jcb.201712058.

    Article  Google Scholar 

  24. Yu IM,Hughson FM. Tethering Factors as Organizers of Intracellular Vesicular Traffic. Annual Review of Cell and Developmental Biology, Vol 26. 2010; doi:https://doi.org/10.1146/annurev.cellbio.042308.113327

  25. Cai HQ, Reinisch K, Ferro-Novick S. Coats, tethers, Rabs, and SNAREs work together to mediate the intracellular destination of a transport vesicle. Dev Cell. 2007. https://doi.org/10.1016/j.devcel.2007.04.005.

    Article  Google Scholar 

  26. Jiang P, Nishimura T, Sakamaki Y, Itakura E, Hatta T, Natsume T, et al. The HOPS complex mediates autophagosome-lysosome fusion through interaction with syntaxin 17. Mol Biol Cell. 2014. https://doi.org/10.1091/mbc.E13-08-0447.

    Article  Google Scholar 

  27. Sun QM, Westphal W, Wong KN, Tan I, Zhong Q. Rubicon controls endosome maturation as a Rab7 effector. Proc Natl Acad Sci USA. 2010. https://doi.org/10.1073/pnas.1010554107.

    Article  Google Scholar 

  28. Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, et al. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol. 2009. https://doi.org/10.1038/ncb1846.

    Article  Google Scholar 

  29. Sil P, Muse G, Martinez J. A ravenous defense: canonical and non-canonical autophagy in immunity. Curr Opin Immunol. 2018. https://doi.org/10.1016/j.coi.2017.10.004.

    Article  Google Scholar 

  30. McEwan DG, Popovic D, Gubas A, Terawaki S, Suzuki H, Stadel D, et al. PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3/GABARAP proteins. Mol Cell. 2015. https://doi.org/10.1016/j.molcel.2014.11.006.

    Article  Google Scholar 

  31. Liang C, Lee JS, Inn KS, Gack MU, Li Q, Roberts EA, et al. Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol. 2008. https://doi.org/10.1038/ncb1740.

    Article  Google Scholar 

  32. Takats S, Toth S, Szenci G, Juhasz G. Investigating Non-selective Autophagy in Drosophila. Methods Mol Biol. 2019. https://doi.org/10.1007/978-1-4939-8873-0_38.

    Article  Google Scholar 

  33. Martens S, Behrends C. Molecular Mechanisms of Selective Autophagy. J Mol Biol. 2020. https://doi.org/10.1016/j.jmb.2019.11.010.

    Article  Google Scholar 

  34. Russell RC, Yuan HX, Guan KL. Autophagy regulation by nutrient signaling. Cell Res. 2014. https://doi.org/10.1038/cr.2013.166.

    Article  Google Scholar 

  35. Grumati P, Dikic I. Ubiquitin signaling and autophagy. J Biol Chem. 2018. https://doi.org/10.1074/jbc.TM117.000117.

    Article  Google Scholar 

  36. Khaminets A, Behl C, Dikic I. Ubiquitin-Dependent And Independent Signals In Selective Autophagy. Trends Cell Biol. 2016. https://doi.org/10.1016/j.tcb.2015.08.010.

    Article  Google Scholar 

  37. Matsumoto G, Wada K, Okuno M, Kurosawa M, Nukina N. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell. 2011. https://doi.org/10.1016/j.molcel.2011.07.039.

    Article  Google Scholar 

  38. Kirkin V, Lamark T, Sou YS, Bjorkoy G, Nunn JL, Bruun JA, et al. A role for NBR1 in autophagosomal degradation of ubiquitinated substrates. Mol Cell. 2009. https://doi.org/10.1016/j.molcel.2009.01.020.

    Article  Google Scholar 

  39. Verstrepen L, Verhelst K, Carpentier I, Beyaert R. TAX1BP1, a ubiquitin-binding adaptor protein in innate immunity and beyond. Trends Biochem Sci. 2011. https://doi.org/10.1016/j.tibs.2011.03.004.

    Article  Google Scholar 

  40. Viret C, Rozieres A, Faure M. Novel Insights into NDP52 Autophagy Receptor Functioning. Trends Cell Biol. 2018. https://doi.org/10.1016/j.tcb.2018.01.003.

    Article  Google Scholar 

  41. Hou P, Yang K, Jia P, Liu L, Lin Y, Li Z, et al. A novel selective autophagy receptor, CCDC50, delivers K63 polyubiquitination-activated RIG-I/MDA5 for degradation during viral infection. Cell Res. 2021. https://doi.org/10.1038/s41422-020-0362-1.

    Article  Google Scholar 

  42. Zhou Z, Liu J, Fu T, Wu P, Peng C, Gong X, et al. Phosphorylation regulates the binding of autophagy receptors to FIP200 Claw domain for selective autophagy initiation. Nat Commun. 2021. https://doi.org/10.1038/s41467-021-21874-1.

    Article  Google Scholar 

  43. Zhang J, Ney PA. Role of BNIP3 and NIX in cell death, autophagy, and mitophagy. Cell Death Differ. 2009. https://doi.org/10.1038/cdd.2009.16.

    Article  Google Scholar 

  44. Yan C, Gong L, Chen L, Xu M, Abou-Hamdan H, Tang M, et al. PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy. 2020. https://doi.org/10.1080/15548627.2019.1628520.

    Article  Google Scholar 

  45. Jiang X, Wang X, Ding X, Du M, Li B, Weng X, et al. FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy. EMBO J. 2020. https://doi.org/10.15252/embj.2019102608.

    Article  Google Scholar 

  46. Chen M, Chen Z, Wang Y, Tan Z, Zhu C, Li Y, et al. Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy. Autophagy. 2016. https://doi.org/10.1080/15548627.2016.1151580.

    Article  Google Scholar 

  47. Borg Distefano M, Hofstad Haugen L, Wang Y, Perdreau-Dahl H, Kjos I, Jia D, et al. TBC1D5 controls the GTPase cycle of Rab7b. J Cell Sci. 2018. https://doi.org/10.1242/jcs.216630.

    Article  Google Scholar 

  48. Jiang S, Wells CD, Roach PJ. Starch-binding domain-containing protein 1 (Stbd1) and glycogen metabolism: Identification of the Atg8 family interacting motif (AIM) in Stbd1 required for interaction with GABARAPL1. Biochem Biophys Res Commun. 2011. https://doi.org/10.1016/j.bbrc.2011.08.106.

    Article  Google Scholar 

  49. Marshall RS, Hua Z, Mali S, McLoughlin F, Vierstra RD. ATG8-Binding UIM Proteins Define a New Class of Autophagy Adaptors and Receptors. Cell. 2019. https://doi.org/10.1016/j.cell.2019.02.009.

    Article  Google Scholar 

  50. Florey O, Overholtzer M. Autophagy proteins in macroendocytic engulfment. Trends Cell Biol. 2012. https://doi.org/10.1016/j.tcb.2012.04.005.

    Article  Google Scholar 

  51. Martinez J, Malireddi RK, Lu Q, Cunha LD, Pelletier S, Gingras S, et al. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat Cell Biol. 2015. https://doi.org/10.1038/ncb3192.

    Article  Google Scholar 

  52. Codogno P, Mehrpour M, Proikas-Cezanne T. Canonical and non-canonical autophagy: variations on a common theme of self-eating? Nat Rev Mol Cell Biol. 2011. https://doi.org/10.1038/nrm3249.

    Article  Google Scholar 

  53. Ponpuak M, Mandell MA, Kimura T, Chauhan S, Cleyrat C, Deretic V. Secretory autophagy. Curr Opin Cell Biol. 2015. https://doi.org/10.1016/j.ceb.2015.04.016.

    Article  Google Scholar 

  54. Kimura T, Jia J, Claude-Taupin A, Kumar S, Choi SW, Gu Y, et al. Cellular and molecular mechanism for secretory autophagy. Autophagy. 2017. https://doi.org/10.1080/15548627.2017.1307486.

    Article  Google Scholar 

  55. Joubert PE, Meiffren G, Gregoire IP, Pontini G, Richetta C, Flacher M, et al. Autophagy induction by the pathogen receptor CD46. Cell Host Microbe. 2009. https://doi.org/10.1016/j.chom.2009.09.006.

    Article  Google Scholar 

  56. Denizot M, Varbanov M, Espert L, Robert-Hebmann V, Sagnier S, Garcia E, et al. HIV-1 gp41 fusogenic function triggers autophagy in uninfected cells. Autophagy. 2008. https://doi.org/10.4161/auto.6880.

    Article  Google Scholar 

  57. Delpeut S, Rudd PA, Labonte P, von Messling V. Membrane fusion-mediated autophagy induction enhances morbillivirus cell-to-cell spread. J Virol. 2012. https://doi.org/10.1128/JVI.00807-12.

    Article  Google Scholar 

  58. Huang H, Kang R, Wang J, Luo G, Yang W, Zhao Z. Hepatitis C virus inhibits AKT-tuberous sclerosis complex (TSC), the mechanistic target of rapamycin (MTOR) pathway, through endoplasmic reticulum stress to induce autophagy. Autophagy. 2013. https://doi.org/10.4161/auto.22791.

    Article  Google Scholar 

  59. Shinohara Y, Imajo K, Yoneda M, Tomeno W, Ogawa Y, Kirikoshi H, et al. Unfolded protein response pathways regulate Hepatitis C virus replication via modulation of autophagy. Biochem Biophys Res Commun. 2013. https://doi.org/10.1016/j.bbrc.2013.01.103.

    Article  Google Scholar 

  60. Medvedev R, Ploen D, Spengler C, Elgner F, Ren H, Bunten S, et al. HCV-induced oxidative stress by inhibition of Nrf2 triggers autophagy and favors release of viral particles. Free Radic Biol Med. 2017. https://doi.org/10.1016/j.freeradbiomed.2017.06.021.

    Article  Google Scholar 

  61. Su WC, Chao TC, Huang YL, Weng SC, Jeng KS, Lai MM. Rab5 and class III phosphoinositide 3-kinase Vps34 are involved in hepatitis C virus NS4B-induced autophagy. J Virol. 2011. https://doi.org/10.1128/JVI.00173-11.

    Article  Google Scholar 

  62. Gregoire IP, Richetta C, Meyniel-Schicklin L, Borel S, Pradezynski F, Diaz O, et al. IRGM Is a Common Target of RNA Viruses that Subvert the Autophagy Network. PLoS Pathog. 2011. https://doi.org/10.1371/journal.ppat.1002422.

    Article  Google Scholar 

  63. Orvedahl A, Alexander D, Talloczy Z, Sun Q, Wei Y, Zhang W, et al. HSV-1 ICP345 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe. 2007. https://doi.org/10.1016/j.chom.2006.12.001.

    Article  Google Scholar 

  64. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 2005. https://doi.org/10.1016/j.cell.2005.07.002.

    Article  Google Scholar 

  65. Mouna L, Hernandez E, Bonte D, Brost R, Amazit L, Delgui LR, et al. Analysis of the role of autophagy inhibition by two complementary human cytomegalovirus BECN1/Beclin 1-binding proteins. Autophagy. 2016. https://doi.org/10.1080/15548627.2015.1125071.

    Article  Google Scholar 

  66. Rubio RM, Mohr I. Inhibition of ULK1 and Beclin1 by an alpha-herpesvirus Akt-like Ser/Thr kinase limits autophagy to stimulate virus replication. Proc Natl Acad Sci U S A. 2019. https://doi.org/10.1073/pnas.1915139116.

    Article  Google Scholar 

  67. Bhatt AP, Damania B. AKTivation of PI3K/AKT/mTOR signaling pathway by KSHV. Front Immunol. 2012. https://doi.org/10.3389/fimmu.2012.00401.

    Article  Google Scholar 

  68. Zhang T, Dong K, Liang W, Xu D, Xia H, Geng J, et al. G-protein-coupled receptors regulate autophagy by ZBTB16-mediated ubiquitination and proteasomal degradation of Atg14L. Elife. 2015. https://doi.org/10.7554/eLife.06734.

    Article  Google Scholar 

  69. Ulasli M, Verheije MH, de Haan CA, Reggiori F. Qualitative and quantitative ultrastructural analysis of the membrane rearrangements induced by coronavirus. Cell Microbiol. 2010. https://doi.org/10.1111/j.1462-5822.2010.01437.x.

    Article  Google Scholar 

  70. Snijder EJ, Limpens R, de Wilde AH, de Jong AWM, Zevenhoven-Dobbe JC, Maier HJ, et al. A unifying structural and functional model of the coronavirus replication organelle: Tracking down RNA synthesis. PLoS Biol. 2020. https://doi.org/10.1371/journal.pbio.3000715.

    Article  Google Scholar 

  71. Knoops K, Kikkert M, van den Worm SHE, Zevenhoven-Dobbe JC, van der Meer Y, Koster AJ, et al. SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum. PLoS Biol. 2008. https://doi.org/10.1371/journal.pbio.0060226.

    Article  Google Scholar 

  72. Cortese M, Lee JY, Cerikan B, Neufeldt CJ, Oorschot VMJ, Kohrer S, et al. Integrative Imaging Reveals SARS-CoV-2-Induced Reshaping of Subcellular Morphologies. Cell Host Microbe. 2020. https://doi.org/10.1016/j.chom.2020.11.003.

    Article  Google Scholar 

  73. Klein S, Cortese M, Winter SL, Wachsmuth-Melm M, Neufeldt CJ, Cerikan B, et al. SARS-CoV-2 structure and replication characterized by in situ cryo-electron tomography. Nat Commun. 2020. https://doi.org/10.1038/s41467-020-19619-7.

    Article  Google Scholar 

  74. Mendonca L, Howe A, Gilchrist JB, Sheng Y, Sun D, Knight ML, et al. Correlative multi-scale cryo-imaging unveils SARS-CoV-2 assembly and egress. Nat Commun. 2021. https://doi.org/10.1038/s41467-021-24887-y.

    Article  Google Scholar 

  75. Wolff G, Limpens R, Zevenhoven-Dobbe JC, Laugks U, Zheng S, de Jong AWM, et al. A molecular pore spans the double membrane of the coronavirus replication organelle. Science. 2020. https://doi.org/10.1126/science.abd3629.

    Article  Google Scholar 

  76. Cottam EM, Maier HJ, Manifava M, Vaux LC, Chandra-Schoenfelder P, Gerner W, et al. Coronavirus nsp6 proteins generate autophagosomes from the endoplasmic reticulum via an omegasome intermediate. Autophagy. 2011. https://doi.org/10.4161/auto.7.11.16642.

    Article  Google Scholar 

  77. Prentice E, Jerome WG, Yoshimori T, Mizushima N, Denison MR. Coronavirus replication complex formation utilizes components of cellular autophagy. J Biol Chem. 2004. https://doi.org/10.1074/jbc.M306124200.

    Article  Google Scholar 

  78. de Haan CA, Reggiori F. Are nidoviruses hijacking the autophagy machinery? Autophagy. 2008. https://doi.org/10.4161/auto.5241.

    Article  Google Scholar 

  79. Snijder EJ, van der Meer Y, Zevenhoven-Dobbe J, Onderwater JJ, van der Meulen J, Koerten HK, et al. Ultrastructure and origin of membrane vesicles associated with the severe acute respiratory syndrome coronavirus replication complex. J Virol. 2006. https://doi.org/10.1128/JVI.02501-05.

    Article  Google Scholar 

  80. Reggiori F, Monastyrska I, Verheije MH, Cali T, Ulasli M, Bianchi S, et al. Coronaviruses Hijack the LC3-I-positive EDEMosomes, ER-derived vesicles exporting short-lived ERAD regulators, for replication. Cell Host Microbe. 2010. https://doi.org/10.1016/j.chom.2010.05.013.

    Article  Google Scholar 

  81. Bernasconi R, Noack J, Molinari M. Unconventional roles of nonlipidated LC3 in ERAD tuning and coronavirus infection. Autophagy. 2012. https://doi.org/10.4161/auto.21229.

    Article  Google Scholar 

  82. Ghosh S, Dellibovi-Ragheb TA, Kerviel A, Pak E, Qiu Q, Fisher M, et al. beta-coronaviruses use lysosomes for egress instead of the biosynthetic secretory pathway. Cell. 2020. https://doi.org/10.1016/j.cell.2020.10.039.

    Article  Google Scholar 

  83. Schlegel A, Giddings TH, Ladinsky MS, Kirkegaard K. Cellular origin and ultrastructure of membranes induced during poliovirus infection. J Virol. 1996. https://doi.org/10.1128/Jvi.70.10.6576-6588.1996.

    Article  Google Scholar 

  84. Jackson WT, Giddings TH, Taylor MP, Mulinyawe S, Rabinovitch M, Kopito RR, et al. Subversion of cellular autophagosomal machinery by RNA viruses. PLoS Biol. 2005. https://doi.org/10.1371/journal.pbio.0030156.

    Article  Google Scholar 

  85. Suhy DA, Giddings TH Jr, Kirkegaard K. Remodeling the endoplasmic reticulum by poliovirus infection and by individual viral proteins: an autophagy-like origin for virus-induced vesicles. J Virol. 2000. https://doi.org/10.1128/jvi.74.19.8953-8965.2000.

    Article  Google Scholar 

  86. Richards AL, Jackson WT. Intracellular vesicle acidification promotes maturation of infectious poliovirus particles. PLoS Pathog. 2012. https://doi.org/10.1371/journal.ppat.1003046.

    Article  Google Scholar 

  87. Richards AL, Soares-Martins JA, Riddell GT, Jackson WT. Generation of unique poliovirus RNA replication organelles. MBio. 2014. https://doi.org/10.1128/mBio.00833-13.

    Article  Google Scholar 

  88. Wong J, Zhang JC, Si XN, Gao G, Mao I, McManus BM, et al. Autophagosome supports coxsackievirus B3 replication in host cells. J Virol. 2008. https://doi.org/10.1128/Jvi.00641-08.

    Article  Google Scholar 

  89. Kemball CC, Alirezaei M, Flynn CT, Wood MR, Harkins S, Kiosses WB, et al. Coxsackievirus infection induces autophagy-like vesicles and megaphagosomes in pancreatic acinar cells in vivo. J Virol. 2010. https://doi.org/10.1128/JVI.01417-10.

    Article  Google Scholar 

  90. Tabor-Godwin JM, Tsueng G, Sayen MR, Gottlieb RA, Feuer R. The role of autophagy during coxsackievirus infection of neural progenitor and stem cells. Autophagy. 2012. https://doi.org/10.4161/auto.19781.

    Article  Google Scholar 

  91. Alirezaei M, Flynn CT, Wood MR, Harkins S, Whitton JL. Coxsackievirus can exploit LC3 in both autophagy-dependent and -independent manners in vivo. Autophagy. 2015. https://doi.org/10.1080/15548627.2015.1063769.

    Article  Google Scholar 

  92. Paul D, Madan V, Ramirez O, Bencun M, Stoeck IK, Jirasko V, et al. Glycine Zipper Motifs in Hepatitis C Virus Nonstructural Protein 4B Are Required for the Establishment of Viral Replication Organelles. J Virol. 2018. https://doi.org/10.1128/JVI.01890-17.

    Article  Google Scholar 

  93. Dreux M, Gastaminza P, Wieland SF, Chisari FV. The autophagy machinery is required to initiate hepatitis C virus replication. Proc Natl Acad Sci USA. 2009. https://doi.org/10.1073/pnas.0907344106.

    Article  Google Scholar 

  94. Doerflinger SY, Cortese M, Romero-Brey I, Menne Z, Tubiana T, Schenk C, et al. Membrane alterations induced by nonstructural proteins of human norovirus. PLoS Pathog. 2017. https://doi.org/10.1371/journal.ppat.1006705.

    Article  Google Scholar 

  95. van der Hoeven B, Oudshoorn D, Koster AJ, Snijder EJ, Kikkert M, Barcena M. Biogenesis and architecture of arterivirus replication organelles. Virus Res. 2016. https://doi.org/10.1016/j.virusres.2016.04.001.

    Article  Google Scholar 

  96. Mohamud Y, Shi JY, Qu JY, Poon T, Xue YC, Deng HY, et al. Enteroviral infection inhibits autophagic flux via disruption of the snare complex to enhance viral replication. Cell Rep. 2018. https://doi.org/10.1016/j.celrep.2018.02.090.

    Article  Google Scholar 

  97. Tian L, Yang YY, Li CY, Chen J, Li ZY, Li X, et al. The cytotoxicity of coxsackievirus B3 is associated with a blockage of autophagic flux mediated by reduced syntaxin 17 expression. Cell Death Dis. 2018. https://doi.org/10.1038/s41419-018-0271-0.

    Article  Google Scholar 

  98. Corona AK, Saulsbery HM, Corona Velazquez AF, Jackson WT. Enteroviruses remodel autophagic trafficking through regulation of Host SNARE proteins to promote virus replication and cell exit. Cell Rep. 2018. https://doi.org/10.1016/j.celrep.2018.03.003.

    Article  Google Scholar 

  99. Mohamud Y, Tang H, Xue YC, Liu HT, Ng CS, Bahreyni A, et al. Coxsackievirus B3 targets TFEB to disrupt lysosomal function. Autophagy. 2021. https://doi.org/10.1080/15548627.2021.1896925.

    Article  Google Scholar 

  100. Gagliardi TB, Goldstein ME, Song D, Gray KM, Jung JW, Ignacio MA, et al. Rhinovirus C replication is associated with the endoplasmic reticulum and triggers cytopathic effects in an in vitro model of human airway epithelium. PLoS Pathog. 2022. https://doi.org/10.1371/journal.ppat.1010159.

    Article  Google Scholar 

  101. Ding BB, Zhang GY, Yang XD, Zhang SW, Chen LY, Yan Q, et al. Phosphoprotein of human parainfluenza virus type 3 blocks autophagosome-lysosome fusion to increase virus production. Cell Host Microbe. 2014. https://doi.org/10.1016/j.chom.2014.04.004.

    Article  Google Scholar 

  102. Wang LY, Tian YJ, Ou JHJ. HCV induces the expression of rubicon and UVRAG to temporally regulate the maturation of autophagosomes and viral replication. PLoS Pathog. 2015. https://doi.org/10.1371/journal.ppat.1004764.

    Article  Google Scholar 

  103. Sir D, Chen WL, Choi J, Wakita T, Yen TSB, Ou JHJ. Induction of incomplete autophagic response by hepatitis C virus via the unfolded protein response. Hepatology. 2008. https://doi.org/10.1002/hep.22464.

    Article  Google Scholar 

  104. Sir D, Liang CY, Chen WL, Jung JU, Ou JHJ. Perturbation of autophagic pathway by hepatitis C virus. Autophagy. 2008. https://doi.org/10.4161/auto.6566.

    Article  Google Scholar 

  105. Taguwa S, Kambara H, Fujita N, Noda T, Yoshimori T, Koike K, et al. Dysfunction of autophagy participates in vacuole formation and cell death in cells replicating hepatitis C Virus. J Virol. 2011. https://doi.org/10.1128/Jvi.06099-11.

    Article  Google Scholar 

  106. Gannage M, Dormann D, Albrecht R, Dengjel J, Torossi T, Ramer PC, et al. Matrix protein 2 of influenza A virus blocks autophagosome fusion with lysosomes. Cell Host Microbe. 2009. https://doi.org/10.1016/j.chom.2009.09.005.

    Article  Google Scholar 

  107. Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT, et al. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol. 2009. https://doi.org/10.1038/ncb1854.

    Article  Google Scholar 

  108. White E. The role for autophagy in cancer. J Clin Invest. 2015. https://doi.org/10.1172/JCI73941.

    Article  Google Scholar 

  109. Wen HJ, Yang Z, Zhou Y, Wood C. Enhancement of autophagy during lytic replication by the Kaposi’s sarcoma-associated herpesvirus replication and transcription activator. J Virol. 2010. https://doi.org/10.1128/JVI.00024-10.

    Article  Google Scholar 

  110. Granato M, Santarelli R, Filardi M, Gonnella R, Farina A, Torrisi MR, et al. The activation of KSHV lytic cycle blocks autophagy in PEL cells. Autophagy. 2015. https://doi.org/10.1080/15548627.2015.1091911.

    Article  Google Scholar 

  111. Granato M, Santarelli R, Farina A, Gonnella R, Lotti LV, Faggioni A, et al. Epstein-barr virus blocks the autophagic flux and appropriates the autophagic machinery to enhance viral replication. J Virol. 2014. https://doi.org/10.1128/JVI.02199-14.

    Article  Google Scholar 

  112. Pringle ES, Robinson CA, McCormick C. Kaposi’s Sarcoma-associated herpesvirus lytic replication interferes with mTORC1 regulation of autophagy and viral protein synthesis. J Virol. 2019. https://doi.org/10.1128/JVI.00854-19.

    Article  Google Scholar 

  113. Zhang Y, Sun H, Pei R, Mao B, Zhao Z, Li H, et al. The SARS-CoV-2 protein ORF3a inhibits fusion of autophagosomes with lysosomes. Cell Discov. 2021. https://doi.org/10.1038/s41421-021-00268-z.

    Article  Google Scholar 

  114. Hayn M, Hirschenberger M, Koepke L, Nchioua R, Straub JH, Klute S, et al. Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities. Cell Rep. 2021. https://doi.org/10.1016/j.celrep.2021.109126.

    Article  Google Scholar 

  115. Hou P, Wang X, Wang H, Wang T, Yu Z, Xu C, et al. The ORF7a protein of SARS-CoV-2 initiates autophagy and limits autophagosome-lysosome fusion via degradation of SNAP29 to promote virus replication. Autophagy. 2022. https://doi.org/10.1080/15548627.2022.2084686.

    Article  Google Scholar 

  116. Singh K, Chen YC, Hassanzadeh S, Han K, Judy JT, Seifuddin F, et al. Network analysis and transcriptome profiling identify autophagic and mitochondrial dysfunctions in SARS-CoV-2 infection. Front Genet. 2021. https://doi.org/10.3389/fgene.2021.599261.

    Article  Google Scholar 

  117. Metz P, Chiramel A, Chatel-Chaix L, Alvisi G, Bankhead P, Mora-Rodriguez R, et al. Dengue virus inhibition of autophagic flux and dependency of viral replication on proteasomal degradation of the autophagy receptor p62. J Virol. 2015. https://doi.org/10.1128/Jvi.00787-15.

    Article  Google Scholar 

  118. Liang QM, Luo ZF, Zeng JX, Chen WQ, Foo SS, Lee SA, et al. Zika Virus NS4A and NS4B proteins deregulate Akt-mTOR signaling in human fetal neural stem cells to inhibit neurogenesis and induce autophagy. Cell Stem Cell. 2016. https://doi.org/10.1016/j.stem.2016.07.019.

    Article  Google Scholar 

  119. Ait-Goughoulte M, Kanda T, Meyer K, Ryerse JS, Ray RB, Ray R. Hepatitis C virus genotype 1a growth and induction of autophagy. J Virol. 2008. https://doi.org/10.1128/JVI.02093-07.

    Article  Google Scholar 

  120. Lin Y, Wu CC, Wang XY, Liu S, Kemper T, Li FH, et al. Synaptosomal-associated protein 29 is required for the autophagic degradation of hepatitis B virus. FASEB J. 2019. https://doi.org/10.1096/fj.201801995RR.

    Article  Google Scholar 

  121. Paul D, Bartenschlager R. Flaviviridae Replication Organelles: Oh, What a Tangled Web We Weave. Ann Rev Virol. 2015. https://doi.org/10.1146/annurev-virology-100114-055007.

    Article  Google Scholar 

  122. Wu YW, Mettling C, Wu SR, Yu CY, Perng GC, Lin YS, et al. Autophagy-associated dengue vesicles promote viral transmission avoiding antibody neutralization. Sci Rep. 2016. https://doi.org/10.1038/srep32243.

    Article  Google Scholar 

  123. Mateo R, Nagamine CM, Spagnolo J, Mendez E, Rahe M, Gale M Jr, et al. Inhibition of cellular autophagy deranges dengue virion maturation. J Virol. 2013. https://doi.org/10.1128/JVI.02177-12.

    Article  Google Scholar 

  124. Li MY, Naik TS, Siu LYL, Acuto O, Spooner E, Wang P, et al. Lyn kinase regulates egress of flaviviruses in autophagosome-derived organelles. Nat Commun. 2020. https://doi.org/10.1038/s41467-020-19028-w.

    Article  Google Scholar 

  125. Bukong TN, Momen-Heravi F, Kodys K, Bala S, Szabo G. Exosomes from hepatitis C infected patients transmit HCV infection and contain replication competent viral RNA in complex with Ago2-miR122-HSP90. PLoS Pathog. 2014. https://doi.org/10.1371/journal.ppat.1004424.

    Article  Google Scholar 

  126. Shrivastava S, Devhare P, Sujijantarat N, Steele R, Kwon YC, Ray R, et al. Knockdown of Autophagy Inhibits Infectious Hepatitis C Virus Release by the Exosomal Pathway. J Virol. 2016. https://doi.org/10.1128/JVI.02383-15.

    Article  Google Scholar 

  127. Zhang ZW, Li ZL, Yuan S. The Role of Secretory Autophagy in Zika Virus Transfer through the Placental Barrier. Front Cell Infect Microbiol. 2016. https://doi.org/10.3389/fcimb.2016.00206.

    Article  Google Scholar 

  128. Vora A, Zhou W, Londono-Renteria B, Woodson M, Sherman MB, Colpitts TM, et al. Arthropod EVs mediate dengue virus transmission through interaction with a tetraspanin domain containing glycoprotein Tsp29Fb. Proc Natl Acad Sci U S A. 2018. https://doi.org/10.1073/pnas.1720125115.

    Article  Google Scholar 

  129. Cao B, Parnell LA, Diamond MS, Mysorekar IU. Inhibition of autophagy limits vertical transmission of Zika virus in pregnant mice. J Exp Med. 2017. https://doi.org/10.1084/jem.20170957.

    Article  Google Scholar 

  130. Chen YH, Du W, Hagemeijer MC, Takvorian PM, Pau C, Cali A, et al. Phosphatidylserine vesicles enable efficient en bloc transmission of enteroviruses. Cell. 2015. https://doi.org/10.1016/j.cell.2015.01.032.

    Article  Google Scholar 

  131. Robinson SM, Tsueng G, Sin J, Mangale V, Rahawi S, McIntyre LL, et al. Coxsackievirus B exits the host cell in shed microvesicles displaying autophagosomal markers. PLoS Pathog. 2014. https://doi.org/10.1371/journal.ppat.1004045.

    Article  Google Scholar 

  132. Bird SW, Maynard ND, Covert MW, Kirkegaard K. Nonlytic viral spread enhanced by autophagy components. Proc Natl Acad Sci U S A. 2014. https://doi.org/10.1073/pnas.1401437111.

    Article  Google Scholar 

  133. Parra GI, Azure J, Fischer R, Bok K, Sandoval-Jaime C, Sosnovtsev SV, et al. Identification of a Broadly Cross-Reactive Epitope in the Inner Shell of the Norovirus Capsid. PLoS ONE. 2013. https://doi.org/10.1371/journal.pone.0067592.

    Article  Google Scholar 

  134. Santiana M, Ghosh S, Ho BA, Rajasekaran V, Du WL, Mutsafi Y, et al. Vesicle-Cloaked Virus Clusters Are Optimal Units for Inter-organismal Viral Transmission. Cell Host Microbe. 2018. https://doi.org/10.1016/j.chom.2018.07.006.

    Article  Google Scholar 

  135. Giansanti P, Strating J, Defourny KAY, Cesonyte I, Bottino AMS, Post H, et al. Dynamic remodelling of the human host cell proteome and phosphoproteome upon enterovirus infection. Nat Commun. 2020. https://doi.org/10.1038/s41467-020-18168-3.

    Article  Google Scholar 

  136. Yan JM, Zhang WK, Yan LN, Jiao YJ, Zhou CM, Yu XJ. Bunyavirus SFTSV exploits autophagic flux for viral assembly and egress. Autophagy. 2022. https://doi.org/10.1080/15548627.2021.1994296.

    Article  Google Scholar 

  137. Nowag H, Guhl B, Thriene K, Romao S, Ziegler U, Dengjel J, et al. Macroautophagy Proteins Assist Epstein Barr Virus Production and Get Incorporated Into the Virus Particles. EBioMedicine. 2014. https://doi.org/10.1016/j.ebiom.2014.11.007.

    Article  Google Scholar 

  138. Hung CH, Chen LW, Wang WH, Chang PJ, Chiu YF, Hung CC, et al. Regulation of autophagic activation by Rta of Epstein-Barr virus via the extracellular signal-regulated kinase pathway. J Virol. 2014. https://doi.org/10.1128/JVI.02033-14.

    Article  Google Scholar 

  139. Zimmermann C, Kramer N, Krauter S, Strand D, Sehn E, Wolfrum U, et al. Autophagy interferes with human cytomegalovirus genome replication, morphogenesis, and progeny release. Autophagy. 2021. https://doi.org/10.1080/15548627.2020.1732686.

    Article  Google Scholar 

  140. Taisne C, Lussignol M, Hernandez E, Moris A, Mouna L, Esclatine A. Human cytomegalovirus hijacks the autophagic machinery and LC3 homologs in order to optimize cytoplasmic envelopment of mature infectious particles. Sci Rep. 2019. https://doi.org/10.1038/s41598-019-41029-z.

    Article  Google Scholar 

  141. Konig P, Svrlanska A, Read C, Feichtinger S, Stamminger T. The autophagy-initiating protein kinase ULK1 phosphorylates human cytomegalovirus tegument protein pp28 and regulates efficient virus release. J Virol. 2021. https://doi.org/10.1128/JVI.02346-20.

    Article  Google Scholar 

  142. Belzile JP, Sabalza M, Craig M, Clark AE, Morello CS, Spector DH. Trehalose, an mTOR-independent inducer of autophagy, inhibits human cytomegalovirus infection in multiple cell types. J Virol. 2016. https://doi.org/10.1128/JVI.02651-15.

    Article  Google Scholar 

  143. Clark AE, Sabalza M, Gordts P, Spector DH. Human Cytomegalovirus replication is inhibited by the autophagy-inducing compounds trehalose and SMER28 through distinctively different mechanisms. J Virol. 2018. https://doi.org/10.1128/JVI.02015-17.

    Article  Google Scholar 

  144. Sabin LR, Hanna SL, Cherry S. Innate antiviral immunity in Drosophila. Curr Opin Immunol. 2010. https://doi.org/10.1016/j.coi.2010.01.007.

    Article  Google Scholar 

  145. Kuo CJ, Hansen M, Troemel E. Autophagy and innate immunity: Insights from invertebrate model organisms. Autophagy. 2018. https://doi.org/10.1080/15548627.2017.1389824.

    Article  Google Scholar 

  146. Shelly S, Lukinova N, Bambina S, Berman A, Cherry S. Autophagy is an essential component of drosophila immunity against vesicular stomatitis virus. Immunity. 2009. https://doi.org/10.1016/j.immuni.2009.02.009.

    Article  Google Scholar 

  147. Moy RH, Gold B, Molleston JM, Schad V, Yanger K, Salzano MV, et al. Antiviral autophagy restricts rift valley fever virus infection and is conserved from flies to mammals. Immunity. 2014. https://doi.org/10.1016/j.immuni.2013.10.020.

    Article  Google Scholar 

  148. Bakowski MA, Desjardins CA, Smelkinson MG, Dunbar TA, Lopez-Moyado IF, Rifkin SA, et al. Ubiquitin-Mediated Response to Microsporidia and Virus Infection in C. elegans. PLoS Pathog. 2014. https://doi.org/10.1371/journal.ppat.1004200.

    Article  Google Scholar 

  149. Orvedahl A, MacPherson S, Sumpter R Jr, Talloczy Z, Zou Z, Levine B. Autophagy protects against Sindbis virus infection of the central nervous system. Cell Host Microbe. 2010. https://doi.org/10.1016/j.chom.2010.01.007.

    Article  Google Scholar 

  150. Miyakawa K, Nishi M, Ogawa M, Matsunaga S, Sugiyama M, Nishitsuji H, et al. Galectin-9 restricts hepatitis B virus replication via p62/SQSTM1-mediated selective autophagy of viral core proteins. Nat Commun. 2022. https://doi.org/10.1038/s41467-022-28171-5.

    Article  Google Scholar 

  151. Sumpter R Jr, Sirasanagandla S, Fernandez AF, Wei Y, Dong X, Franco L, et al. Fanconi anemia proteins function in mitophagy and immunity. Cell. 2016. https://doi.org/10.1016/j.cell.2016.04.006.

    Article  Google Scholar 

  152. Fletcher K, Ulferts R, Jacquin E, Veith T, Gammoh N, Arasteh JM, et al. The WD40 domain of ATG16L1 is required for its non-canonical role in lipidation of LC3 at single membranes. EMBO J. 2018. https://doi.org/10.15252/embj.201797840.

    Article  Google Scholar 

  153. Wang Y, Sharma P, Jefferson M, Zhang W, Bone B, Kipar A, et al. Non-canonical autophagy functions of ATG16L1 in epithelial cells limit lethal infection by influenza A virus. EMBO J. 2021. https://doi.org/10.15252/embj.2020105543.

    Article  Google Scholar 

  154. Cadwell K, Patel KK, Maloney NS, Liu TC, Ng AC, Storer CE, et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell. 2010. https://doi.org/10.1016/j.cell.2010.05.009.

    Article  Google Scholar 

  155. Moroso M, Verlhac P, Ferraris O, Rozieres A, Carbonnelle C, Mely S, et al. Crimean-Congo hemorrhagic fever virus replication imposes hyper-lipidation of MAP1LC3 in epithelial cells. Autophagy. 2020. https://doi.org/10.1080/15548627.2019.1709765.

    Article  Google Scholar 

  156. Durgan J, Lystad AH, Sloan K, Carlsson SR, Wilson MI, Marcassa E, et al. Non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine. Mol Cell. 2021. https://doi.org/10.1016/j.molcel.2021.03.020.

    Article  Google Scholar 

  157. Xu Y, Shen J, Ran Z. Emerging views of mitophagy in immunity and autoimmune diseases. Autophagy. 2020. https://doi.org/10.1080/15548627.2019.1603547.

    Article  Google Scholar 

  158. Ng CS, Kato H, Fujita T. Fueling Type I interferonopathies: regulation and function of type i interferon antiviral responses. J Interferon Cytokine Res. 2019. https://doi.org/10.1089/jir.2019.0037.

    Article  Google Scholar 

  159. Tal MC, Sasai M, Lee HK, Yordy B, Shadel GS, Iwasaki A. Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc Natl Acad Sci U S A. 2009. https://doi.org/10.1073/pnas.0807694106.

    Article  Google Scholar 

  160. Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011. https://doi.org/10.1038/nature09663.

    Article  Google Scholar 

  161. Rawat P, Teodorof-Diedrich C, Spector SA. Human immunodeficiency virus Type-1 single-stranded RNA activates the NLRP3 inflammasome and impairs autophagic clearance of damaged mitochondria in human microglia. Glia. 2019. https://doi.org/10.1002/glia.23568.

    Article  Google Scholar 

  162. Teodorof-Diedrich C, Spector SA. Human immunodeficiency virus type 1 gp120 and tat induce mitochondrial fragmentation and incomplete mitophagy in human neurons. J Virol. 2018. https://doi.org/10.1128/JVI.00993-18.

    Article  Google Scholar 

  163. Thangaraj A, Periyasamy P, Liao K, Bendi VS, Callen S, Pendyala G, et al. HIV-1 TAT-mediated microglial activation: role of mitochondrial dysfunction and defective mitophagy. Autophagy. 2018. https://doi.org/10.1080/15548627.2018.1476810.

    Article  Google Scholar 

  164. Vo MT, Smith BJ, Nicholas J, Choi YB. Activation of NIX-mediated mitophagy by an interferon regulatory factor homologue of human herpesvirus. Nat Commun. 2019. https://doi.org/10.1038/s41467-019-11164-2.

    Article  Google Scholar 

  165. Wang RF, Zhu YX, Ren CW, Yang SK, Tian S, Chen HC, et al. Influenza A virus protein PB1-F2 impairs innate immunity by inducing mitophagy. Autophagy. 2020. https://doi.org/10.1080/15548627.2020.1725375.

    Article  Google Scholar 

  166. Sato-Kaneko F, Yao S, Lao FS, Nan J, Shpigelman J, Cheng A, et al. Mitochondria-dependent synthetic small-molecule vaccine adjuvants for influenza virus infection. Proc Natl Acad Sci U S A. 2021. https://doi.org/10.1073/pnas.2025718118.

    Article  Google Scholar 

  167. Vilmen G, Glon D, Siracusano G, Lussignol M, Shao Z, Hernandez E, et al. BHRF1, a BCL2 viral homolog, disturbs mitochondrial dynamics and stimulates mitophagy to dampen type I IFN induction. Autophagy. 2021. https://doi.org/10.1080/15548627.2020.1758416.

    Article  Google Scholar 

  168. Ding BB, Zhang LL, Li ZF, Zhong Y, Tang QP, Qin YL, et al. The Matrix Protein of Human Parainfluenza Virus Type 3 Induces Mitophagy that Suppresses Interferon Responses. Cell Host Microbe. 2017. https://doi.org/10.1016/j.chom.2017.03.004.

    Article  Google Scholar 

  169. Sun D, Kong N, Dong S, Chen X, Qin W, Wang H, et al. 2AB protein of Senecavirus A antagonizes selective autophagy and type I interferon production by degrading LC3 and MARCHF8. Autophagy. 2022. https://doi.org/10.1080/15548627.2021.2015740.

    Article  Google Scholar 

  170. Hui X, Zhang L, Cao L, Huang K, Zhao Y, Zhang Y, et al. SARS-CoV-2 promote autophagy to suppress type I interferon response. Signal Transduct Target Ther. 2021. https://doi.org/10.1038/s41392-021-00574-8.

    Article  Google Scholar 

  171. Li X, Hou P, Ma W, Wang X, Wang H, Yu Z, et al. SARS-CoV-2 ORF10 suppresses the antiviral innate immune response by degrading MAVS through mitophagy. Cell Mol Immunol. 2022. https://doi.org/10.1038/s41423-021-00807-4.

    Article  Google Scholar 

  172. Ramachandran K, Maity S, Muthukumar AR, Kandala S, Tomar D, Abd El-Aziz TM, et al. SARS-CoV-2 infection enhances mitochondrial PTP complex activity to perturb cardiac energetics. iScience. 2022. https://doi.org/10.1016/j.isci.2021.103722.

    Article  Google Scholar 

  173. Lupfer C, Thomas PG, Anand PK, Vogel P, Milasta S, Martinez J, et al. Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection. Nat Immunol. 2013. https://doi.org/10.1038/ni.2563.

    Article  Google Scholar 

  174. Wang R, Zhu Y, Lin X, Ren C, Zhao J, Wang F, et al. Influenza M2 protein regulates MAVS-mediated signaling pathway through interacting with MAVS and increasing ROS production. Autophagy. 2019. https://doi.org/10.1080/15548627.2019.1580089.

    Article  Google Scholar 

  175. Misawa T, Takahama M, Saitoh T. Mitochondria-endoplasmic reticulum contact sites mediate innate immune responses. Organelle Contact Sites: Mol Mechanism to Disease. 2017. https://doi.org/10.1007/978-981-10-4567-7_14.

    Article  Google Scholar 

  176. Pinar A, Dowling JK, Bitto NJ, Robertson AAB, Latz E, Stewart CR, et al. PB1-F2 Peptide Derived from Avian Influenza A Virus H7N9 Induces Inflammation via Activation of the NLRP3 Inflammasome. J Biol Chem. 2017. https://doi.org/10.1074/jbc.M116.756379.

    Article  Google Scholar 

  177. Subramanian N, Natarajan K, Clatworthy MR, Wang Z, Germain RN. The Adaptor MAVS Promotes NLRP3 Mitochondrial Localization and Inflammasome Activation. Cell. 2013. https://doi.org/10.1016/j.cell.2013.02.054.

    Article  Google Scholar 

  178. Yoshizumi T, Ichinohe T, Sasaki O, Otera H, Kawabata SI, Mihara K, et al. Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity. Nat Commun. 2014. https://doi.org/10.1038/ncomms5713.

    Article  Google Scholar 

  179. Kuo SM, Chen CJ, Chang SC, Liu TJ, Chen YH, Huang SY, et al. Inhibition of Avian Influenza A Virus Replication in Human Cells by Host Restriction Factor TUFM Is Correlated with Autophagy. MBio. 2017. https://doi.org/10.1128/mBio.00481-17.

    Article  Google Scholar 

  180. Zeng Y, Xu S, Wei Y, Zhang X, Wang Q, Jia Y, et al. The PB1 protein of influenza A virus inhibits the innate immune response by targeting MAVS for NBR1-mediated selective autophagic degradation. PLoS Pathog. 2021. https://doi.org/10.1371/journal.ppat.1009300.

    Article  Google Scholar 

  181. Wilkinson S. ER-phagy: shaping up and destressing the endoplasmic reticulum. FEBS J. 2019. https://doi.org/10.1111/febs.14932.

    Article  Google Scholar 

  182. Lennemann NJ, Coyne CB. Dengue and Zika viruses subvert reticulophagy by NS2B3-mediated cleavage of FAM134B. Autophagy. 2017. https://doi.org/10.1080/15548627.2016.1265192.

    Article  Google Scholar 

  183. Chiramel AI, Dougherty JD, Nair V, Robertson SJ, Best SM. FAM134B, the Selective Autophagy Receptor for Endoplasmic Reticulum Turnover, Inhibits Replication of Ebola Virus Strains Makona and Mayinga. J Infect Dis. 2016. https://doi.org/10.1093/infdis/jiw270.

    Article  Google Scholar 

  184. Evans AS, Lenneman NJ, Coyne CB. BPIFB3 Regulates Endoplasmic Reticulum Morphology To Facilitate Flavivirus Replication. J Virol. 2020. https://doi.org/10.1128/JVI.00029-20.

    Article  Google Scholar 

  185. Grumati P, Morozzi G, Holper S, Mari M, Harwardt MI, Yan R, et al. Full length RTN3 regulates turnover of tubular endoplasmic reticulum via selective autophagy. Elife. 2017. https://doi.org/10.7554/eLife.25555.

    Article  Google Scholar 

  186. Aktepe TE, Liebscher S, Prier JE, Simmons CP, Mackenzie JM. The Host Protein Reticulon 3.1A Is Utilized by Flaviviruses to Facilitate Membrane Remodelling. Cell Rep. 2017. https://doi.org/10.1016/j.celrep.2017.10.055.

    Article  Google Scholar 

  187. Wu MJ, Ke PY, Hsu JTA, Yeh CT, Horng JT. Reticulon 3 interacts with NS4B of the hepatitis C virus and negatively regulates viral replication by disrupting NS4B self-interaction. Cell Microbiol. 2014. https://doi.org/10.1111/cmi.12318.

    Article  Google Scholar 

  188. Saito T, Kuma A, Sugiura Y, Ichimura Y, Obata M, Kitamura H, et al. Autophagy regulates lipid metabolism through selective turnover of NCoR1. Nat Commun. 2019. https://doi.org/10.1038/s41467-019-08829-3.

    Article  Google Scholar 

  189. Kaur J, Debnath J. Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol. 2015. https://doi.org/10.1038/nrm4024.

    Article  Google Scholar 

  190. Martin S, Parton RG. Lipid droplets: a unified view of a dynamic organelle. Nat Rev Mol Cell Biol. 2006. https://doi.org/10.1038/nrm1912.

    Article  Google Scholar 

  191. Heaton NS, Randall G. Dengue virus-induced autophagy regulates lipid metabolism. Cell Host Microbe. 2010. https://doi.org/10.1016/j.chom.2010.10.006.

    Article  Google Scholar 

  192. Zhang JS, Lan Y, Li MY, Lamers MM, Fusade-Boyer M, Klemm E, et al. Flaviviruses exploit the lipid droplet protein AUP1 to trigger lipophagy and drive virus production. Cell Host Microbe. 2018. https://doi.org/10.1016/j.chom.2018.05.005.

    Article  Google Scholar 

  193. Heaton NS, Perera R, Berger KL, Khadka S, LaCount DJ, Kuhn RJ, et al. Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. Proc Natl Acad Sci USA. 2010. https://doi.org/10.1073/pnas.1010811107.

    Article  Google Scholar 

  194. Cloherty APM, Olmstead AD, Ribeiro CMS, Jean F. Hijacking of Lipid Droplets by Hepatitis C, Dengue and Zika Viruses-From Viral Protein Moonlighting to Extracellular Release. Int J Mol Sci. 2020. https://doi.org/10.3390/ijms21217901.

    Article  Google Scholar 

  195. Yoon MJ, Choi B, Kim EJ, Ohk J, Yang C, Choi YG, et al. UXT chaperone prevents proteotoxicity by acting as an autophagy adaptor for p62-dependent aggrephagy. Nat Commun. 2021. https://doi.org/10.1038/s41467-021-22252-7.

    Article  Google Scholar 

  196. Cuanalo-Contreras K, Moreno-Gonzalez I. Natural products as modulators of the proteostasis machinery: implications in neurodegenerative diseases. Int J Mol Sci. 2019. https://doi.org/10.3390/ijms20194666.

    Article  Google Scholar 

  197. Muscolino E, Schmitz R, Loroch S, Caragliano E, Schneider C, Rizzato M, et al. Herpesviruses induce aggregation and selective autophagy of host signalling proteins NEMO and RIPK1 as an immune-evasion mechanism. Nat Microbiol. 2020. https://doi.org/10.1038/s41564-019-0624-1.

    Article  Google Scholar 

  198. Pantopoulos K, Porwal SK, Tartakoe A, Devireddy L. Mechanisms of mammalian iron homeostasis. Biochemistry. 2012. https://doi.org/10.1021/bi300752r.

    Article  Google Scholar 

  199. Mancias JD, Vaites LP, Nissim S, Biancur DE, Kim AJ, Wang XX, et al. Ferritinophagy via NCOA4 is required for erythropoiesis and is regulated by iron dependent HERC2-mediated proteolysis. Elife. 2015. https://doi.org/10.7554/eLife.10308.

    Article  Google Scholar 

  200. Bartolomei G, Cevik RE, Marcello A. Modulation of hepatitis C virus replication by iron and hepcidin in Huh7 hepatocytes. J Gen Virol. 2011. https://doi.org/10.1099/vir.0.032706-0.

    Article  Google Scholar 

  201. Terpiowska S, Siwicki AK. Chromium(III) and iron(III) inhibits replication of DNA and RNA viruses. Biometals. 2017. https://doi.org/10.1007/s10534-017-0027-9.

    Article  Google Scholar 

  202. Georgiou NA, van der Bruggen T, Oudshoorn M, Nottet HSLM, Marx JJM, van Asbeck BS. Inhibition of human immunodeficiency virus type 1 replication in human mononuclear blood cells by the iron chelators deferoxamine, deferiprone, and bleomycin. J Infect Dis. 2000. https://doi.org/10.1086/315223.

    Article  Google Scholar 

  203. Duchemin JB, Paradkar PN. Iron availability affects West Nile virus infection in its mosquito vector. Virol J. 2017. https://doi.org/10.1186/s12985-017-0770-0.

    Article  Google Scholar 

  204. Sun Y, Bao Q, Xuan B, Xu W, Pan D, Li Q, et al. Human Cytomegalovirus Protein pUL38 Prevents Premature Cell Death by Binding to Ubiquitin-Specific Protease 24 and Regulating Iron Metabolism. J Virol. 2018. https://doi.org/10.1128/JVI.00191-18.

    Article  Google Scholar 

  205. Ohta K, Saka N, Nishio M. Human Parainfluenza Virus Type 2 V Protein Modulates Iron Homeostasis. J Virol. 2021. https://doi.org/10.1128/JVI.01861-20.

    Article  Google Scholar 

  206. Sumpter R, Levine B. Autophagy and innate immunity: Triggering, targeting and tuning. Semin Cell Dev Biol. 2010. https://doi.org/10.1016/j.semcdb.2010.04.003.

    Article  Google Scholar 

  207. Lee MS, Kim YJ. Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu Rev Biochem. 2007. https://doi.org/10.1146/annurev.biochem.76.060605.122847.

    Article  Google Scholar 

  208. Choi Y, Bowman JW, Jung JU. Autophagy during viral infection - a double-edged sword. Nat Rev Microbiol. 2018. https://doi.org/10.1038/s41579-018-0003-6.

    Article  Google Scholar 

  209. Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014. https://doi.org/10.3389/fimmu.2014.00461.

    Article  Google Scholar 

  210. Qian Y, Commane M, Ninomiya-Tsuji J, Matsumoto K, Li X. IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B. J Biol Chem. 2001. https://doi.org/10.1074/jbc.M102262200.

    Article  Google Scholar 

  211. Rasmussen SB, Horan KA, Holm CK, Stranks AJ, Mettenleiter TC, Simon AK, et al. Activation of autophagy by alpha-herpesviruses in myeloid cells is mediated by cytoplasmic viral DNA through a mechanism dependent on stimulator of IFN genes. J Immunol. 2011. https://doi.org/10.4049/jimmunol.1100949.

    Article  Google Scholar 

  212. Parker ZM, Murphy AA, Leib DA. Role of the DNA Sensor STING in Protection from Lethal Infection following Corneal and Intracerebral Challenge with Herpes Simplex Virus 1. J Virol. 2015. https://doi.org/10.1128/JVI.00954-15.

    Article  Google Scholar 

  213. Zhang R, Kang R, Tang D. The STING1 network regulates autophagy and cell death. Signal Transduct Target Ther. 2021. https://doi.org/10.1038/s41392-021-00613-4.

    Article  Google Scholar 

  214. Lee NR, Ban J, Lee NJ, Yi CM, Choi JY, Kim H, et al. Activation of RIG-I-Mediated Antiviral Signaling Triggers Autophagy Through the MAVS-TRAF6-Beclin-1 Signaling Axis. Front Immunol. 2018. https://doi.org/10.3389/fimmu.2018.02096.

    Article  Google Scholar 

  215. Liu S, Chen J, Cai X, Wu J, Chen X, Wu YT, et al. MAVS recruits multiple ubiquitin E3 ligases to activate antiviral signaling cascades. Elife. 2013. https://doi.org/10.7554/eLife.00785.

    Article  Google Scholar 

  216. Fang R, Jiang Q, Zhou X, Wang C, Guan Y, Tao J, et al. MAVS activates TBK1 and IKKepsilon through TRAFs in NEMO dependent and independent manner. PLoS Pathog. 2017. https://doi.org/10.1371/journal.ppat.1006720.

    Article  Google Scholar 

  217. Shi CS, Kehrl JH. MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. J Biol Chem. 2008. https://doi.org/10.1074/jbc.M804478200.

    Article  Google Scholar 

  218. Yang Q, Liu TT, Lin H, Zhang M, Wei J, Luo WW, et al. TRIM32-TAX1BP1-dependent selective autophagic degradation of TRIF negatively regulates TLR3/4-mediated innate immune responses. PLoS Pathog. 2017. https://doi.org/10.1371/journal.ppat.1006600.

    Article  Google Scholar 

  219. Takeuchi O, Akira S. Innate immunity to virus infection. Immunol Rev. 2009. https://doi.org/10.1111/j.1600-065X.2008.00737.x.

    Article  Google Scholar 

  220. West AP, Shadel GS, Ghosh S. Mitochondria in innate immune responses. Nat Rev Immunol. 2011. https://doi.org/10.1038/nri2975.

    Article  Google Scholar 

  221. Biasizzo M, Kopitar-Jerala N. Interplay Between NLRP3 Inflammasome and Autophagy. Front Immunol. 2020. https://doi.org/10.3389/fimmu.2020.591803.

    Article  Google Scholar 

  222. Yang CS, Rodgers M, Min CK, Lee JS, Kingeter L, Lee JY, et al. The Autophagy Regulator Rubicon Is a Feedback Inhibitor of CARD9-Mediated Host Innate Immunity. Cell Host Microbe. 2012. https://doi.org/10.1016/j.chom.2012.01.019.

    Article  Google Scholar 

  223. Lee HK, Lund JM, Ramanathan B, Mizushima N, Iwasaki A. Autophagy-dependent viral recognition by plasmacytoid dendritic cells. Science. 2007. https://doi.org/10.1126/science.1136880.

    Article  Google Scholar 

  224. de Carvalho RVH, Lima-Junior DS, da Silva MVG, Dilucca M, Rodrigues TS, Horta CV, et al. Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition. Nat Commun. 2019. https://doi.org/10.1038/s41467-019-13356-2.

    Article  Google Scholar 

  225. Yordy B, Tal MC, Hayashi K, Arojo O, Iwasaki A. Autophagy and selective deployment of Atg proteins in antiviral defense. Int Immunol. 2013. https://doi.org/10.1093/intimm/dxs101.

    Article  Google Scholar 

  226. Zhang R, Qin X, Yang Y, Zhu X, Zhao S, Zhang Z, et al. STING1 is essential for an RNA-virus triggered autophagy. Autophagy. 2022. https://doi.org/10.1080/15548627.2021.1959086.

    Article  Google Scholar 

  227. Liu Y, Gordesky-Gold B, Leney-Greene M, Weinbren NL, Tudor M, Cherry S. Inflammation-Induced, STING-Dependent Autophagy Restricts Zika Virus Infection in the Drosophila Brain. Cell Host Microbe. 2018. https://doi.org/10.1016/j.chom.2018.05.022.

    Article  Google Scholar 

  228. Delorme-Axford E, Klionsky DJ. Inflammatory-dependent Sting activation induces antiviral autophagy to limit zika virus in the Drosophila brain. Autophagy. 2019. https://doi.org/10.1080/15548627.2018.1539585.

    Article  Google Scholar 

  229. Chan ST, Lee J, Narula M, Ou JJ. Suppression of Host Innate Immune Response by Hepatitis C Virus via Induction of Autophagic Degradation of TRAF6. J Virol. 2016. https://doi.org/10.1128/JVI.01365-16.

    Article  Google Scholar 

  230. Chandra PK, Bao LL, Song K, Aboulnasr FM, Baker DP, Shores N, et al. HCV Infection Selectively Impairs Type I but Not Type III IFN Signaling. Am J Pathol. 2014. https://doi.org/10.1016/j.ajpath.2013.10.005.

    Article  Google Scholar 

  231. Liang QM, Seo GJ, Choi YJ, Kwak MJ, Ge JN, Rodgers MA, et al. Crosstalk between the cGAS DNA Sensor and Beclin-1 Autophagy Protein Shapes Innate Antimicrobial Immune Responses. Cell Host Microbe. 2014. https://doi.org/10.1016/j.chom.2014.01.009.

    Article  Google Scholar 

  232. Xie W, Tian S, Yang J, Cai S, Jin S, Zhou T, et al. OTUD7B deubiquitinates SQSTM1/p62 and promotes IRF3 degradation to regulate antiviral immunity. Autophagy. 2022. https://doi.org/10.1080/15548627.2022.2026098.

    Article  Google Scholar 

  233. Blum JS, Wearsch PA, Cresswell P. Pathways of Antigen Processing. Ann Rev Immunol. 2013. https://doi.org/10.1146/annurev-immunol-032712-095910.

    Article  Google Scholar 

  234. Lich JD, Elliott JF, Blum JS. Cytoplasmic processing is a prerequisite for presentation of an endogenous antigen by major histocompatibility complex class II proteins. J Exp Med. 2000. https://doi.org/10.1084/jem.191.9.1513.

    Article  Google Scholar 

  235. Tewari MK, Sinnathamby G, Rajagopal D, Eisenlohr LC. A cytosolic pathway for MHC class II-restricted antigen processing that is proteasome and TAP dependent (vol 6, pg 287, 2005). Nat Immunol. 2005. https://doi.org/10.1038/ni0405-420.

    Article  Google Scholar 

  236. Dahl SW, Halkier T, Lauritzen C, Dolenc I, Pedersen J, Turk V, et al. Human recombinant pro-dipeptidyl peptidase I (cathepsin C) can be activated by cathepsins L and S but not by autocatalytic processing. Biochemistry. 2001. https://doi.org/10.1021/bi001693z.

    Article  Google Scholar 

  237. Munz C. Antigen processing via autophagy–not only for MHC class II presentation anymore? Curr Opin Immunol. 2010. https://doi.org/10.1016/j.coi.2010.01.016.

    Article  Google Scholar 

  238. Valecka J, Almeida CR, Su B, Pierre P, Gatti E. Autophagy and MHC-restricted antigen presentation. Mol Immunol. 2018. https://doi.org/10.1016/j.molimm.2018.05.009.

    Article  Google Scholar 

  239. Loi M, Muller A, Steinbach K, Niven J, da Silva RB, Paul P, et al. Macroautophagy Proteins Control MHC Class I Levels on Dendritic Cells and Shape Anti-viral CD8(+) T Cell Responses. Cell Rep. 2016. https://doi.org/10.1016/j.celrep.2016.04.002.

    Article  Google Scholar 

  240. Parekh VV, Pabbisetty SK, Wu L, Sebzda E, Martinez J, Zhang JH, et al. Autophagy-related protein Vps34 controls the homeostasis and function of antigen cross-presenting CD8 alpha(+) dendritic cells. Proc Natl Acad Sci USA. 2017. https://doi.org/10.1073/pnas.1706504114.

    Article  Google Scholar 

  241. Yamamoto K, Venida A, Yano J, Biancur DE, Kakiuchi M, Gupta S, et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature. 2020. https://doi.org/10.1038/s41586-020-2229-5.

    Article  Google Scholar 

  242. Tey SK, Khanna R. Autophagy mediates transporter associated with antigen processing-independent presentation of viral epitopes through MHC class I pathway. Blood. 2012. https://doi.org/10.1182/blood-2012-01-402404.

    Article  Google Scholar 

  243. Wenger T, Terawaki S, Camosseto V, Abdelrassoul R, Mies A, Catalan N, et al. Autophagy inhibition promotes defective neosynthesized proteins storage in ALIS, and induces redirection toward proteasome processing and MHCI-restricted presentation. Autophagy. 2012. https://doi.org/10.4161/auto.18806.

    Article  Google Scholar 

  244. Schmid D, Pypaert M, Munz C. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity. 2007. https://doi.org/10.1016/j.immuni.2006.10.018.

    Article  Google Scholar 

  245. Comber JD, Robinson TM, Siciliano NA, Snook AE, Eisenlohr LC. Functional Macroautophagy Induction by Influenza A Virus without a Contribution to Major Histocompatibility Complex Class II-Restricted Presentation. J Virol. 2011. https://doi.org/10.1128/Jvi.02122-10.

    Article  Google Scholar 

  246. Jin Y, Sun C, Feng L, Li P, Xiao L, Ren Y, et al. Regulation of SIV antigen-specific CD4+ T cellular immunity via autophagosome-mediated MHC II molecule-targeting antigen presentation in mice. PLoS ONE. 2014. https://doi.org/10.1371/journal.pone.0093143.

    Article  Google Scholar 

  247. Blanchet FP, Moris A, Nikolic DS, Lehmann M, Cardinaud S, Stalder R, et al. Human immunodeficiency virus-1 inhibition of immunoamphisomes in dendritic cells impairs early innate and adaptive immune responses. Immunity. 2010. https://doi.org/10.1016/j.immuni.2010.04.011.

    Article  Google Scholar 

  248. Zhang Y, Chen Y, Li Y, Huang F, Luo B, Yuan Y, et al. The ORF8 protein of SARS-CoV-2 mediates immune evasion through down-regulating MHC-Iota. Proc Natl Acad Sci U S A. 2021. https://doi.org/10.1073/pnas.2024202118.

    Article  Google Scholar 

  249. English L, Chemali M, Desjardins M. Nuclear membrane-derived autophagy, a novel process that participates in the presentation of endogenous viral antigens during HSV-1 infection. Autophagy. 2009. https://doi.org/10.4161/auto.5.7.9163.

    Article  Google Scholar 

  250. Dong XN, Yang YT, Zou ZJ, Zhao YT, Ci B, Zhong L, et al. Sorting nexin 5 mediates virus-induced autophagy and immunity. Nature. 2020. https://doi.org/10.1038/s41586-020-03056-z.

    Article  Google Scholar 

  251. Schuchman R, Kilianski A, Piper A, Vancini R, Ribeiro JMC, Sprague TR, et al. Comparative Characterization of the Sindbis Virus Proteome from Mammalian and Invertebrate Hosts Identifies nsP2 as a Component of the Virion and Sorting Nexin 5 as a Significant Host Factor for Alphavirus Replication. J Virol. 2018. https://doi.org/10.1128/JVI.00694-18.

    Article  Google Scholar 

  252. Nanbo A, Imai M, Watanabe S, Noda T, Takahashi K, Neumann G, et al. Ebolavirus is internalized into host cells via macropinocytosis in a viral glycoprotein-dependent manner. PLoS Pathog. 2010. https://doi.org/10.1371/journal.ppat.1001121.

    Article  Google Scholar 

  253. Feng ZK, Kovalev N, Nagy PD. Key interplay between the co-opted sorting nexin-BAR proteins and PI3P phosphoinositide in the formation of the tombusvirus replicase. PLoS Pathog. 2020. https://doi.org/10.1371/journal.ppat.1009120.

    Article  Google Scholar 

  254. Maschkowitz G, Gartner S, Hofmann-Winkler H, Fickenscher H, Winkler M. Interaction of Human Cytomegalovirus Tegument Proteins ppUL35 and ppUL35A with Sorting Nexin 5 Regulates Glycoprotein B (gpUL55) Localization. J Virol. 2018. https://doi.org/10.1128/JVI.00013-18.

    Article  Google Scholar 

Download references

Acknowledgements

We thank X. Xiao (Huazhong Agricultural University, China) for critically proofreading the manuscript. We sincerely apologize for not citing all relevant papers related to this review owing to space limitations. The figures are created with Biorender.com.

Funding

This work was supported by the National Key Research and Development Program (2021YFD1800204), the National Natural Science Foundation of China (32025036 and 31772752), the earmarked fund for CARS-41, and the Natural Science Foundation of Hubei Province (2021CFA016).

Author information

Authors and Affiliations

Authors

Contributions

HZ, MJ, HC and TC conceived the project, TC, ST and ND conducted and wrote the manuscript of this review. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hongbo Zhou.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, T., Tu, S., Ding, L. et al. The role of autophagy in viral infections. J Biomed Sci 30, 5 (2023). https://doi.org/10.1186/s12929-023-00899-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12929-023-00899-2

Keywords

  • Autophagy degradation
  • Immune response
  • Selective autophagy
  • Viral infection
  • Viral replication