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The S1/S2 boundary of SARS-CoV-2 spike protein modulates cell entry pathways and transmission

By Yunkai Zhu, Fei Feng, Gaowei Hu, Yuyan Wang, Yin Yu, Yuanfei Zhu, Wei Xu, Xia Cai, Zhiping Sun, Wendong Han, Rong Ye, Hongjun Chen, Qiang Ding, Qiliang Cai, Di Qu, Youhua Xie, Zhenghong Yuan, Rong Zhang

Posted 25 Aug 2020
bioRxiv DOI: 10.1101/2020.08.25.266775

The global spread of SARS-CoV-2 is posing major public health challenges. One unique feature of SARS-CoV-2 spike protein is the insertion of multi-basic residues at the S1/S2 subunit cleavage site, the function of which remains uncertain. We found 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 instead utilizes a less efficient endosomal entry pathway. This idea was supported by the identification of a suite of endosomal entry factors specific to Sdel virus by a genome-wide CRISPR-Cas9 screen. A panel of host factors regulating the surface expression of ACE2 was identified for both viruses. Using a hamster model, animal-to-animal transmission with the Sdel virus was almost completely abrogated, unlike with Sfull. These findings highlight the critical role of the S1/S2 boundary of the SARS-CoV-2 spike protein in modulating virus entry and transmission. ### Competing Interest Statement The authors have declared no competing interest.

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