tetano
Editor, Senior Moderator
Nat Commun
. 2021 Feb 11;12(1):961.
doi: 10.1038/s41467-021-21213-4.
A genome-wide CRISPR screen identifies host factors that regulate SARS-CoV-2 entry
Yunkai Zhu[SUP] #[/SUP][SUP] 1 [/SUP], Fei Feng[SUP] #[/SUP][SUP] 1 [/SUP], Gaowei Hu[SUP] #[/SUP][SUP] 1 [/SUP], Yuyan Wang[SUP] #[/SUP][SUP] 1 [/SUP], Yin Yu[SUP] 1 [/SUP], Yuanfei Zhu[SUP] 1 [/SUP], Wei Xu[SUP] 1 [/SUP], Xia Cai[SUP] 1 [/SUP], Zhiping Sun[SUP] 1 [/SUP], Wendong Han[SUP] 1 [/SUP], Rong Ye[SUP] 1 [/SUP], Di Qu[SUP] 1 [/SUP], Qiang Ding[SUP] 2 [/SUP], Xinxin Huang[SUP] 3 [/SUP], Hongjun Chen[SUP] 4 [/SUP], Wei Xu[SUP] 5 [/SUP], Youhua Xie[SUP] 1 [/SUP], Qiliang Cai[SUP] 6 [/SUP], Zhenghong Yuan[SUP] 7 [/SUP], Rong Zhang[SUP] 8 [/SUP]
Affiliations
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.
. 2021 Feb 11;12(1):961.
doi: 10.1038/s41467-021-21213-4.
A genome-wide CRISPR screen identifies host factors that regulate SARS-CoV-2 entry
Yunkai Zhu[SUP] #[/SUP][SUP] 1 [/SUP], Fei Feng[SUP] #[/SUP][SUP] 1 [/SUP], Gaowei Hu[SUP] #[/SUP][SUP] 1 [/SUP], Yuyan Wang[SUP] #[/SUP][SUP] 1 [/SUP], Yin Yu[SUP] 1 [/SUP], Yuanfei Zhu[SUP] 1 [/SUP], Wei Xu[SUP] 1 [/SUP], Xia Cai[SUP] 1 [/SUP], Zhiping Sun[SUP] 1 [/SUP], Wendong Han[SUP] 1 [/SUP], Rong Ye[SUP] 1 [/SUP], Di Qu[SUP] 1 [/SUP], Qiang Ding[SUP] 2 [/SUP], Xinxin Huang[SUP] 3 [/SUP], Hongjun Chen[SUP] 4 [/SUP], Wei Xu[SUP] 5 [/SUP], Youhua Xie[SUP] 1 [/SUP], Qiliang Cai[SUP] 6 [/SUP], Zhenghong Yuan[SUP] 7 [/SUP], Rong Zhang[SUP] 8 [/SUP]
Affiliations
- PMID: 33574281
- DOI: 10.1038/s41467-021-21213-4
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.