SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation

Proc Natl Acad Sci U S A. 2022 Aug 9;119(32):e2204539119. doi: 10.1073/pnas.2204539119. Epub 2022 Jul 25.

Abstract

Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-β. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-β production, which inhibits SARS-CoV-2 replication. Our findings reveal a target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.

Keywords: 4EHP; GIGYF2; NSP2; SARS-CoV-2; mRNA translation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19* / genetics
  • Carrier Proteins* / metabolism
  • Cell Line
  • Eukaryotic Initiation Factor-4E / metabolism
  • Humans
  • Immunity, Innate
  • Interferon Type I* / metabolism
  • Protein Biosynthesis
  • RNA, Messenger / genetics
  • SARS-CoV-2
  • Viral Nonstructural Proteins* / metabolism
  • Virus Replication

Substances

  • Carrier Proteins
  • EIF4E2 protein, human
  • Eukaryotic Initiation Factor-4E
  • GIGYF2 protein, human
  • Interferon Type I
  • RNA, Messenger
  • Viral Nonstructural Proteins
  • nsp2 protein, SARS-CoV-2