Fig. 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