A genome-wide CRISPR screen identifies host factors that regulate SARS-CoV-2 entry

Yunkai Zhu, Fei Feng, Gaowei Hu, Yuyan Wang, Yin Yu, Yuanfei Zhu, Wei Xu, Xia Cai, Zhiping Sun, Wendong Han, Rong Ye, Di Qu, Qiang Ding, Xinxin Huang, Hongjun Chen, Wei Xu, Youhua Xie, Qiliang Cai (), Zhenghong Yuan () and Rong Zhang ()
Additional contact information
Yunkai Zhu: Fudan University
Fei Feng: Fudan University
Gaowei Hu: Fudan University
Yuyan Wang: Fudan University
Yin Yu: Fudan University
Yuanfei Zhu: Fudan University
Wei Xu: Fudan University
Xia Cai: Fudan University
Zhiping Sun: Fudan University
Wendong Han: Fudan University
Rong Ye: Fudan University
Di Qu: Fudan University
Qiang Ding: Tsinghua University
Xinxin Huang: Plant and Food Inspection and Quarantine of Shanghai Customs
Hongjun Chen: CAAS
Wei Xu: Southern Medical University
Youhua Xie: Fudan University
Qiliang Cai: Fudan University
Zhenghong Yuan: Fudan University
Rong Zhang: Fudan University

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract The global spread of SARS-CoV-2 is posing major public health challenges. One feature of SARS-CoV-2 spike protein is the insertion of multi-basic residues at the S1/S2 subunit cleavage site. Here, we find that the virus with intact spike (Sfull) preferentially enters cells via fusion at the plasma membrane, whereas a clone (Sdel) with deletion disrupting the multi-basic S1/S2 site utilizes an endosomal entry pathway. Using Sdel as model, we perform a genome-wide CRISPR screen and identify several endosomal entry-specific regulators. Experimental validation of hits from the CRISPR screen shows that host factors regulating the surface expression of angiotensin-converting enzyme 2 (ACE2) affect entry of Sfull virus. Animal-to-animal transmission with the Sdel virus is reduced compared to Sfull in the hamster model. These findings highlight the critical role of the S1/S2 boundary of SARS-CoV-2 spike protein in modulating virus entry and transmission and provide insights into entry of coronaviruses.

Date: 2021
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DOI: 10.1038/s41467-021-21213-4

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