Gene

Coronavirus

ATG16L1

Cell biology

Linguistics

Philosophy

Biology

Lysosome

Virology

Apoptosis

Autophagy

Biochemistry

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Coronavirus disease 2019 (COVID-19)

Autophagosome

Intracellular

Endosome

Fusion

Enzyme

Infectious disease (medical specialty)

Vacuolar protein sorting

Lipid bilayer fusion

Medicine

Chemistry

Virus

Fusion protein

Disease

Protein degradation

Recombinant DNA

Pathology

Cell Discovery

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing coronavirus disease 2019 pandemic. How SARS-CoV-2 regulates cellular responses to escape clearance by host cells is unknown. Autophagy is an intracellular lysosomal degradation pathway for the clearance of various cargoes, including viruses. Here, we systematically screened 28 viral proteins of SARS-CoV-2 and identified that ORF3a strongly inhibited autophagic flux by blocking the fusion of autophagosomes with lysosomes. ORF3a colocalized with lysosomes and interacted with VPS39, a component of the homotypic fusion and protein sorting (HOPS) complex. The ORF3a-VPS39 interaction prohibited the binding of HOPS with RAB7, which prevented the assembly of fusion machinery, leading to the accumulation of unfused autophagosomes. These results indicated the potential mechanism by which SARS-CoV-2 escapes degradation; that is, the virus interferes with autophagosome-lysosome fusion. Furthermore, our findings will facilitate strategies targeting autophagy for conferring potential protection against the spread of SARS-CoV-2.

The SARS-CoV-2 protein ORF3a inhibits fusion of autophagosomes with lysosomes