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ORF3a of SARS-CoV-2 promotes lysosomal exocytosis-mediated viral egress
Developmental Cell  (IF12.27),  Pub Date : 2021-10-11, DOI: 10.1016/j.devcel.2021.10.006
Di Chen, Qiaoxia Zheng, Long Sun, Mingming Ji, Yan Li, Hongyu Deng, Hong Zhang

Viral entry and egress are important determinants of virus infectivity and pathogenicity. β-Coronaviruses, including the COVID-19 virus SARS-CoV-2 and MHV, exploit the lysosomal exocytosis pathway for egress. Here we show that SARS-CoV-2 ORF3a, but not SARS-CoV ORF3a, promotes lysosomal exocytosis. SARS-CoV-2 ORF3a facilitates lysosomal targeting of the BORC-ARL8b complex, which mediates trafficking of lysosomes to the vicinity of the plasma membrane, and exocytosis-related SNARE proteins. The Ca2+ channel TRPML3 is required for SARS-CoV-2 ORF3a-mediatd lysosomal exocytosis. Expression of SARS-CoV-2 ORF3a greatly elevates extracellular viral release in cells infected with the coronavirus MHV-A59 which itself lacks ORF3a. In SARS-CoV-2 ORF3a, Ser171 and Trp193 are critical for promoting lysosomal exocytosis and blocking autophagy. When these residues are introduced into SARS-CoV ORF3a, it acquires the ability to promote lysosomal exocytosis and inhibit autophagy. Our results reveal a mechanism by which SARS-CoV-2 interacts with host factors to promote its extracellular egress.