Regulation of autophagy by SARS‐CoV‐2: The multifunctional contributions of ORF3a

Abstract Severe acute respiratory syndrome‐coronavirus‐2 (SARS‐CoV‐2) regulates autophagic flux by blocking the fusion of autophagosomes with lysosomes, causing the accumulation of membranous vesicles for replication. Multiple SARS‐CoV‐2 proteins regulate autophagy with significant roles attributed to ORF3a. Mechanistically, open reading frame 3a (ORF3a) forms a complex with UV radiation resistance associated, regulating the functions of the PIK3C3‐1 and PIK3C3‐2 lipid kinase complexes, thereby modulating autophagosome biogenesis. ORF3a sequesters VPS39 onto the late endosome/lysosome, inhibiting assembly of the soluble NSF attachement protein REceptor (SNARE) complex and preventing autolysosome formation. ORF3a promotes the interaction between BECN1 and HMGB1, inducing the assembly of PIK3CA kinases into the ER (endoplasmic reticulum) and activating reticulophagy, proinflammatory responses, and ER stress. ORF3a recruits BORCS6 and ARL8B to lysosomes, initiating the anterograde transport of the virus to the plasma membrane. ORF3a also activates the SNARE complex (STX4‐SNAP23‐VAMP7), inducing fusion of lysosomes with the plasma membrane for viral egress. These mechanistic details can provide multiple targets for inhibiting SARS‐CoV‐2 by developing host‐ or host–pathogen interface‐based therapeutics.