Fig. 6: Schematic diagram of the function of SARS-CoV-2 ORF3a in blocking autophagosome–lysosome fusion.
From: The SARS-CoV-2 protein ORF3a inhibits fusion of autophagosomes with lysosomes
Upper, after double-layered autophagosomes are formed, they fuse with lysosomes for final degradation of their cargoes. GTPase RAB7 recruits the tethering HOPS complex, acting as a bridge to bring the two compartments together. These tethering HOPS complexes, in turn, help SNAREs physically drive the fusion of opposing lipid bilayers. Lower, when host cells are subjected to SARS-CoV-2 infection, ORF3a is expressed and interacts with VPS39. The ORF3a–VPS39 interaction sequesters VPS39, preventing its interaction with RAB7 and resulting in failure of HOPS–RAB7 assembly and blockage of autophagosome–lysosome fusion, which eventually leads to accumulation of autophagosomes.
