Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation

Proc Natl Acad Sci U S A. 2021 Nov 23;118(47):e2109905118. doi: 10.1073/pnas.2109905118.

Abstract

The SARS-CoV-2 coronavirus responsible for the global pandemic contains a novel furin cleavage site in the spike protein (S) that increases viral infectivity and syncytia formation in cells. Here, we show that O-glycosylation near the furin cleavage site is mediated by members of the GALNT enzyme family, resulting in decreased furin cleavage and decreased syncytia formation. Moreover, we show that O-glycosylation is dependent on the novel proline at position 681 (P681). Mutations of P681 seen in the highly transmissible alpha and delta variants abrogate O-glycosylation, increase furin cleavage, and increase syncytia formation. Finally, we show that GALNT family members capable of glycosylating S are expressed in human respiratory cells that are targets for SARS-CoV-2 infection. Our results suggest that host O-glycosylation may influence viral infectivity/tropism by modulating furin cleavage of S and provide mechanistic insight into the role of the P681 mutations found in the highly transmissible alpha and delta variants.

Keywords: COVID-19; O-; SARS-CoV-2; furin; glycosylation; spike.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cell Fusion
  • Cell Line
  • Furin / metabolism
  • Giant Cells
  • Glycosylation
  • Humans
  • N-Acetylgalactosaminyltransferases / metabolism
  • Polypeptide N-acetylgalactosaminyltransferase
  • SARS-CoV-2 / genetics
  • SARS-CoV-2 / metabolism*
  • Spike Glycoprotein, Coronavirus / genetics
  • Spike Glycoprotein, Coronavirus / metabolism*

Substances

  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • N-Acetylgalactosaminyltransferases
  • Furin