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ORF3a mediated-incomplete autophagy facilitates SARS-CoV-2 replication

By Yafei Qu, Xin Wang, Yunkai Zhu, Yuyan Wang, Xing Yang, Gaowei Hu, Chengrong Liu, Jingjiao Li, Shanhui Ren, Zixuan Xiao, Zhenshan Liu, Weili Wang, Ping Li, Rong Zhang, Qiming Liang

Posted 12 Nov 2020
bioRxiv DOI: 10.1101/2020.11.12.380709

SARS-CoV-2 is the causative agent for the COVID-19 pandemic and there is an urgent need to understand the cellular response to SARS-CoV-2 infection. Beclin-1 is an essential scaffold autophagy protein that forms two distinct subcomplexes with modulators Atg14 and UVRAG, responsible for autophagosome formation and maturation, respectively. In the present study, we found that SARS-CoV-2 infection triggers an incomplete autophagy response, elevated autophagosome formation but impaired autophagosome maturation, and declined autophagy by genetic knockout of essential autophagic genes reduces SARS-CoV-2 replication efficiency. By screening 28 viral proteins of SARS-CoV-2, we demonstrated that expression of ORF3a alone is sufficient to induce incomplete autophagy. Mechanistically, SARS-CoV-2 ORF3a interacts with autophagy regulator UVRAG to facilitate Beclin-1-Vps34-Atg14 complex but selectively inhibit Beclin-1-Vps34-UVRAG complex. Interestingly, although SARS-CoV ORF3a shares 72.7% amino acid identity with the SARS-CoV-2 ORF3a, the former had no effect on cellular autophagy response. Thus, our findings provide the mechanistic evidence of possible takeover of host autophagy machinery by ORF3a to facilitate SARS-CoV-2 replication and raises the possibility of targeting the autophagic pathway for the treatment of COVID-19. ### Competing Interest Statement The authors have declared no competing interest.

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