Opposing activities of IFITM proteins in SARS-CoV-2 infection

EMBO J. 2021 Feb 1;40(3):e106501. doi: 10.15252/embj.2020106501. Epub 2020 Dec 21.

Abstract

Interferon-induced transmembrane proteins (IFITMs) restrict infections by many viruses, but a subset of IFITMs enhance infections by specific coronaviruses through currently unknown mechanisms. We show that SARS-CoV-2 Spike-pseudotyped virus and genuine SARS-CoV-2 infections are generally restricted by human and mouse IFITM1, IFITM2, and IFITM3, using gain- and loss-of-function approaches. Mechanistically, SARS-CoV-2 restriction occurred independently of IFITM3 S-palmitoylation, indicating a restrictive capacity distinct from reported inhibition of other viruses. In contrast, the IFITM3 amphipathic helix and its amphipathic properties were required for virus restriction. Mutation of residues within the IFITM3 endocytosis-promoting YxxФ motif converted human IFITM3 into an enhancer of SARS-CoV-2 infection, and cell-to-cell fusion assays confirmed the ability of endocytic mutants to enhance Spike-mediated fusion with the plasma membrane. Overexpression of TMPRSS2, which increases plasma membrane fusion versus endosome fusion of SARS-CoV-2, attenuated IFITM3 restriction and converted amphipathic helix mutants into infection enhancers. In sum, we uncover new pro- and anti-viral mechanisms of IFITM3, with clear distinctions drawn between enhancement of viral infection at the plasma membrane and amphipathicity-based mechanisms used for endosomal SARS-CoV-2 restriction.

Keywords: COVID-19; IFITM; IFITM3; SARS-CoV-2; interferon.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Angiotensin-Converting Enzyme 2 / genetics
  • Animals
  • Antigens, Differentiation / genetics*
  • COVID-19 / genetics*
  • Cell Line
  • Chlorocebus aethiops
  • Humans
  • Membrane Proteins / genetics*
  • Mice
  • Mutation
  • RNA-Binding Proteins / genetics*
  • SARS-CoV-2* / physiology
  • Serine Endopeptidases
  • Virus Internalization

Substances

  • Antigens, Differentiation
  • IFITM2 protein, human
  • IFITM3 protein, human
  • Membrane Proteins
  • RNA-Binding Proteins
  • leu-13 antigen
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Serine Endopeptidases
  • TMPRSS2 protein, human