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Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion.


ABSTRACT: Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infects cells by binding to the host cell receptor ACE2 and undergoing virus-host membrane fusion. Fusion is triggered by the protease TMPRSS2, which processes the viral Spike (S) protein to reveal the fusion peptide. SARS-CoV-2 has evolved a multibasic site at the S1-S2 boundary, which is thought to be cleaved by furin in order to prime S protein for TMPRSS2 processing. Here we show that CRISPR-Cas9 knockout of furin reduces, but does not prevent, the production of infectious SARS-CoV-2 virus. Comparing S processing in furin knockout cells to multibasic site mutants reveals that while loss of furin substantially reduces S1-S2 cleavage it does not prevent it. SARS-CoV-2 S protein also mediates cell-cell fusion, potentially allowing virus to spread virion-independently. We show that loss of furin in either donor or acceptor cells reduces, but does not prevent, TMPRSS2-dependent cell-cell fusion, unlike mutation of the multibasic site that completely prevents syncytia formation. Our results show that while furin promotes both SARS-CoV-2 infectivity and cell-cell spread it is not essential, suggesting furin inhibitors may reduce but not abolish viral spread.

SUBMITTER: Papa G 

PROVIDER: S-EPMC7861537 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion.

Papa Guido G   Mallery Donna L DL   Albecka Anna A   Welch Lawrence G LG   Cattin-Ortolá Jérôme J   Luptak Jakub J   Paul David D   McMahon Harvey T HT   Goodfellow Ian G IG   Carter Andrew A   Munro Sean S   James Leo C LC  

PLoS pathogens 20210125 1


Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infects cells by binding to the host cell receptor ACE2 and undergoing virus-host membrane fusion. Fusion is triggered by the protease TMPRSS2, which processes the viral Spike (S) protein to reveal the fusion peptide. SARS-CoV-2 has evolved a multibasic site at the S1-S2 boundary, which is thought to be cleaved by furin in order to prime S protein for TMPRSS2 processing. Here we show that CRISPR-Cas9 knockout of furin reduces, but does  ...[more]

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