Fig. 4
From: Role and clinical implication of autophagy in COVID-19
Modulation of coronavirus in the autophagy pathway
Although viral infections can trigger autophagy in antiviral immune responses to limit the virus replication cycle and infection process, the surviving viruses can evolve various strategies to inhibit multiple steps of the autophagy pathways or utilize autophagy to escape immune clearance, and even hijack autophagy to provide shelter to their offspring and obtain energy for replication. TGEV infection can induce autophagy. Some studies suggest that pharmacological or genetic inhibition of autophagy increased TGEV replication, whereas other studies have reported that TGEV-activated mitophagy supports cell survival and possibly viral infection. The PLpro of SARS-CoV-2 disrupts autophagy and induces viral pathogenesis by significantly decreasing ULK1 expression. MERS-CoV blocked the autophagic flux by decreasing BECN1 levels mediated by SKP2. IBV or NSP6 protein of MHV and SARS, or NSP5, NSP6, and NSP7 of arterivirus PRRSV could reduce the number of viral components transported from autophagosomes to lysosomes by promoting the generation of autophagosomes with a smaller diameter. The accessory protein ORF3a of SARS-CoV-2 weakens autophagy activity by inhibiting the fusion of autophagosomes/amphisomes with lysosomes. The key to this fusion is the STX17-SNAP29-VAMP8 SNARE complex, whose assembly can be blocked by the interaction of the HOPS complex with ORF3a instead of the autophagosomal SNARE protein STX17. Expression of both SARS-CoV-2 ORF3a and β-coronaviruses can damage lysosomes by impairing their functions including degradation and digestion. The replication of SARS-CoV and MHV could be independent of autophagy, during which the virus hijacked the pathway of EDEMosome formation to produce nonlipidated LC3-I coated DMVs for replication
Abbreviations: BECN1: beclin1; DMV: double-membrane vesicle; MCoV: Mouse coronavirus; MERS-CoV: Middle East respiratory syndrome coronavirus; MHV: Mouse hepatitis virus; NSP: nonstructural proteins; ORFs: open reading frames; PLpro: papain-like protease; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SKP2: S-phase kinase-associated protein 2; TGEV: transmissible gastroenteritis virus; ULK1: unc-51 like autophagy activating kinase 1