Frontiers in Cell and Developmental Biology (Jul 2021)

ORF3a-Mediated Incomplete Autophagy Facilitates Severe Acute Respiratory Syndrome Coronavirus-2 Replication

  • Yafei Qu,
  • Xin Wang,
  • Yunkai Zhu,
  • Weili Wang,
  • Yuyan Wang,
  • Gaowei Hu,
  • Chengrong Liu,
  • Jingjiao Li,
  • Shanhui Ren,
  • Maggie Z. X. Xiao,
  • Zhenshan Liu,
  • Chunxia Wang,
  • Joyce Fu,
  • Yucai Zhang,
  • Ping Li,
  • Rong Zhang,
  • Qiming Liang,
  • Qiming Liang,
  • Qiming Liang

DOI
https://doi.org/10.3389/fcell.2021.716208
Journal volume & issue
Vol. 9

Abstract

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Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the causative agent for the coronavirus disease 2019 (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 26 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 PI3KC3-C1 (Beclin-1-Vps34-Atg14) but selectively inhibit PI3KC3-C2 (Beclin-1-Vps34-UVRAG). 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 raise the possibility of targeting the autophagic pathway for the treatment of COVID-19.

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