tetano
Editor, Senior Moderator
PLoS Pathog
. 2021 Jan 25;17(1):e1009246.
doi: 10.1371/journal.ppat.1009246. Online ahead of print.
Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion
Guido Papa[SUP] 1 [/SUP], Donna L Mallery[SUP] 1 [/SUP], Anna Albecka[SUP] 1 [/SUP], Lawrence G Welch[SUP] 1 [/SUP], J?r?me Cattin-Ortol?[SUP] 1 [/SUP], Jakub Luptak[SUP] 1 [/SUP], David Paul[SUP] 1 [/SUP], Harvey T McMahon[SUP] 1 [/SUP], Ian G Goodfellow[SUP] 2 [/SUP], Andrew Carter[SUP] 1 [/SUP], Sean Munro[SUP] 1 [/SUP], Leo C James[SUP] 1 [/SUP]
Affiliations
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.
. 2021 Jan 25;17(1):e1009246.
doi: 10.1371/journal.ppat.1009246. Online ahead of print.
Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion
Guido Papa[SUP] 1 [/SUP], Donna L Mallery[SUP] 1 [/SUP], Anna Albecka[SUP] 1 [/SUP], Lawrence G Welch[SUP] 1 [/SUP], J?r?me Cattin-Ortol?[SUP] 1 [/SUP], Jakub Luptak[SUP] 1 [/SUP], David Paul[SUP] 1 [/SUP], Harvey T McMahon[SUP] 1 [/SUP], Ian G Goodfellow[SUP] 2 [/SUP], Andrew Carter[SUP] 1 [/SUP], Sean Munro[SUP] 1 [/SUP], Leo C James[SUP] 1 [/SUP]
Affiliations
- PMID: 33493182
- DOI: 10.1371/journal.ppat.1009246
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.