A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells

Mol Cell. 2020 May 21;78(4):779-784.e5. doi: 10.1016/j.molcel.2020.04.022. Epub 2020 May 1.

Abstract

The pandemic coronavirus SARS-CoV-2 threatens public health worldwide. The viral spike protein mediates SARS-CoV-2 entry into host cells and harbors a S1/S2 cleavage site containing multiple arginine residues (multibasic) not found in closely related animal coronaviruses. However, the role of this multibasic cleavage site in SARS-CoV-2 infection is unknown. Here, we report that the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. Moreover, optimizing the S1/S2 site increased cell-cell, but not virus-cell, fusion, suggesting that the corresponding viral variants might exhibit increased cell-cell spread and potentially altered virulence. Our results suggest that acquisition of a S1/S2 multibasic cleavage site was essential for SARS-CoV-2 infection of humans and identify furin as a potential target for therapeutic intervention.

Keywords: COVID-19; S1/S2; SARS-CoV-2; TMPRSS2; cleavage; entry; furin; membrane fusion; spike.

MeSH terms

  • Animals
  • Betacoronavirus / chemistry*
  • Betacoronavirus / physiology
  • COVID-19
  • Cell Line
  • Chlorocebus aethiops
  • Coronavirus Infections / virology*
  • Furin / chemistry
  • Furin / genetics
  • Furin / metabolism
  • Humans
  • Lung / metabolism
  • Lung / virology
  • Pandemics
  • Pneumonia, Viral / virology*
  • SARS-CoV-2
  • Serine Endopeptidases / metabolism
  • Spike Glycoprotein, Coronavirus / chemistry*
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / metabolism
  • Vero Cells
  • Virus Attachment

Substances

  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Serine Endopeptidases
  • TMPRSS2 protein, human
  • FURIN protein, human
  • Furin