Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2

Science. 2020 Sep 4;369(6508):1249-1255. doi: 10.1126/science.abc8665. Epub 2020 Jul 17.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. A major virulence factor of SARS-CoVs is the nonstructural protein 1 (Nsp1), which suppresses host gene expression by ribosome association. Here, we show that Nsp1 from SARS-CoV-2 binds to the 40S ribosomal subunit, resulting in shutdown of messenger RNA (mRNA) translation both in vitro and in cells. Structural analysis by cryo-electron microscopy of in vitro-reconstituted Nsp1-40S and various native Nsp1-40S and -80S complexes revealed that the Nsp1 C terminus binds to and obstructs the mRNA entry tunnel. Thereby, Nsp1 effectively blocks retinoic acid-inducible gene I-dependent innate immune responses that would otherwise facilitate clearance of the infection. Thus, the structural characterization of the inhibitory mechanism of Nsp1 may aid structure-based drug design against SARS-CoV-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Betacoronavirus / chemistry*
  • Betacoronavirus / immunology
  • Betacoronavirus / metabolism
  • Betacoronavirus / physiology
  • Binding Sites
  • COVID-19
  • Coronavirus Infections / immunology
  • Coronavirus Infections / virology
  • Cryoelectron Microscopy
  • DEAD Box Protein 58 / genetics
  • DEAD Box Protein 58 / metabolism
  • Humans
  • Immune Evasion*
  • Immunity, Innate*
  • Interferon-beta / genetics
  • Interferon-beta / metabolism
  • Models, Molecular
  • Pandemics
  • Pneumonia, Viral / immunology
  • Pneumonia, Viral / virology
  • Protein Binding
  • Protein Biosynthesis*
  • Protein Domains
  • Protein Interaction Domains and Motifs
  • Protein Structure, Secondary
  • RNA, Messenger / metabolism
  • Receptors, Immunologic
  • Ribosome Subunits, Small, Eukaryotic / chemistry
  • Ribosome Subunits, Small, Eukaryotic / metabolism
  • SARS-CoV-2
  • Viral Nonstructural Proteins / chemistry*
  • Viral Nonstructural Proteins / metabolism*

Substances

  • NSP1 protein, SARS-CoV-2
  • RNA, Messenger
  • Receptors, Immunologic
  • Viral Nonstructural Proteins
  • Interferon-beta
  • RIGI protein, human
  • DEAD Box Protein 58