Table 5 Post-translational modification and regulation of ACE2 protein
From: ACE2 in chronic disease and COVID-19: gene regulation and post-translational modification
Post-translational modification and regulation of ACE2 protein | ||
|---|---|---|
Name | Description | Ref. |
Phosphorylation | ||
 AMPK | AMPK mediates ACE2 Ser680 phosphorylation, inhibiting MDM2-mediated ACE2 ubiquitination | |
 CK1α | CK1α phosphorylates ACE2 (3SSS5) and induces the binding of E3 ligase SPOP to ACE2, leading to prevention of ACE2 protein from other E3 ligase-mediated protein degradation Infection of SARS-CoV-2 is attenuated by the CK1α inhibitor lenalidomide ACE2 protein levels are decreased by the CK1α inhibitor D4476, epiblastin A, and lenalidomide | [147] |
 MAP4K3 (GLK) | GLK phosphorylates ACE2 Ser776 and Ser783, leading to inhibition of UBR4-mediated ACE2 ubiquitination GLK expression is induced in the epithelial cells from COVID-19 patients ACE2 protein levels are decreased by the GLK inhibitor verteporfin | [28] |
 NUAK2 | NUAK2 maintains ACE2 proteins on cell surface, resulting in enhancement of SARS-CoV-2 infection Surface ACE2 protein levels are decreased by the NUAK2 inhibitor WZ-4003 | [149] |
Ubiquitination/deubiquitination | ||
 MDM2 | MDM2 induces ACE2 ubiquitination at Lys788, resulting in proteasomal degradation of ACE2 protein MDM2-mediated ubiquitination is inhibited by AMPK-induced ACE2 phosphorylation MDM2 levels are induced in the lung tissues from IPAH patients ACE2 protein levels are increased by the MDM2 inhibitor JNJ-26854165 (JNJ-165) | [125] |
 NEDD4L | Ang II may decreases ACE2 protein levels through NEDD4L-mediated ubiquitination | [126] |
 Skp2 | Skp2 induces ACE2 ubiquitination and degradation Skp2 expression is induced through the tobacco carcinogen BaP ACE2 protein levels are increased by inhibition Skp2 through the CDK4/6 inhibitor palbociclib | |
 UBR4 | USBR4 induces ubiquitination of ACE2 protein at Lys26, Lys112, and Lys114, leading to proteasomal degradation of ACE2 protein UBR4-mediated ubiquitination is inhibited by GLK-induced ACE2 phosphorylation during SARS-CoV-2 infection | [28] |
 UCHL1 | SARS-CoV-2 S protein stabilizes ACE2 protein through UCHL1-mediated deubiquitination, contributing to enhancement of SARS-CoV-2 infection ACE2 protein levels are decreased by the UCHL1 inhibitor LDN-57444 | [29] |
 SPOP | The E3 ligase SPOP binds to CK1α-phosphorylated ACE2 at 1MSSSS5 residues, leading to prevention of ACE2 protein from other E3 ligase-mediated protein degradation | [147] |
 USP50 | USP50 is a deubiquitinase that removes ubiquitins from its target proteins USP50 reduces ACE2 Lys48-linked ubiquitination at Lys788 residue and enhances ACE2 protein stability Vit C inhibits USP50-mediated ACE2 deubiquitination, resulting in downregulation of ACE2 proteins and attenuation of SARS-CoV-2 infection | [153] |
Exosomal regulation | ||
 MAP4K3 (GLK) | GLK induces exosomal ACE2 in COVID-19 patients GLK expression is induced in the lung epithelial cells from COVID-19 patient | [28] |
Ectodomain shedding | ||
 ADAM17 | ADAM17 induces ACE2 ectodomain shedding and turns ACE2 into the catalytic activity-retaining soluble form ADAM17 cleavage sites on the ACE2 protein are at the region between ACE2 Ser716 and Ile741 residue or individual Ser709, Leu584, Arg652, Lys657, and Lys659 The soluble ACE2 protein levels are increased in the urine of human type 1 or type 2 diabetes patients and in the peripheral blood of myocardial infarction-induced heart failure patients Soluble ACE2 binds to SARS-CoV-2 S protein, facilitating cell entry of SARS-CoV-2 through receptor-mediated endocytosis Soluble ACE2 protein levels are decreased by the metalloproteinase inhibitor GM6001, as well as ADAM17 inhibitors GW280264X, DPC333, and TIMP-3 | |
Lysosomal degradation | ||
 AP2 | High concentration of SARS-CoV-2 S protein induces ACE2 lysosomal degradation through AP2/clatherin-mediated endocytosis | [166] |
SUMOylation | ||
 PIAS4 | The E3 ligase PIAS4 induces SUMO3 SUMOylation of ACE2 protein, preventing ACE2 autophagy ACE2 SUMO3 SUMOylation is mainly induced at Lys187 | [169] |
 SENP3 | SENP3-mediated deSUMOylation decreases ACE2 protein levels, contributing to attenuation of SARS-CoV-2 virus infection | [169] |
Arginine methylation | ||
 PRMT5 | PRMT5 induces ACE2 protein methylation at Arg671, facilitating SARS-CoV-2 infection Infection of SARS-CoV-2 is attenuated by the PRMT5 inhibitor GSK3326595 | [170] |