Editors' ChoiceCORONAVIRUS

Autophagy chokes on SARS-CoV-2

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Science Signaling  09 Mar 2021:
Vol. 14, Issue 673, eabh3628
DOI: 10.1126/scisignal.abh3628

SARS-CoV-2 ORF3a prevents autophagosome-lysosome fusion.

Autophagy is a key mechanism for clearing pathogens, and many bacteria and viruses have evolved strategies for interfering with the formation or maturation of autophagosomes in host cells. Miao et al. systematically evaluated the effects of proteins encoded by SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic, on autophagy. Infection of HeLa cells with intact SARS-CoV-2 or expression of the SARS-CoV-2 transmembrane protein ORF3a inhibited autophagy by blocking the fusion of autophagosomes and amphisomes (autophagosomes that have fused with endosomes) with lysosomes. ORF3a mainly localized to late endosomes and lysosomes in cells and interacted indirectly with several members of the homotypic fusion and protein sorting (HOPS) complex and directly with the HOPS component VPS39 in vitro. The HOPS complex is present on late endosomes and lysosomes and interacts with SNARE proteins on autophagosomes to promote the formation of fusion-competent SNARE complexes. ORF3a localized with VPS39, caused VPS39 and other components of the HOPS complex to accumulate on late endosomes and lysosomes, and reduced the formation of SNARE complexes by interfering with the interaction between the HOPS complex and the autophagosomal SNARE component STX17. Inducing the formation of SNARE complexes by knocking down OGT, an O-linked β-N-acetyl-glucosamine (O-GlcNAc) transferase that inhibits SNARE complex formation, rescued the autophagy defects in ORF3a-expressing cells. Inhibition of autophagy and interaction with VPS39 were not observed with ORF3a from SARS-CoV. The authors also identified three other SARS-CoV-2 proteins that interfered with host cell autophagy (see Yim and Mizushima), suggesting that blocking this cellular defense pathway is important for SARS-CoV-2 survival and replication in host cells.

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