SARS-CoV-2 Membrane Protein Inhibits Type I Interferon Production Through Ubiquitin-Mediated Degradation of TBK1

Front Immunol. 2021 May 18:12:662989. doi: 10.3389/fimmu.2021.662989. eCollection 2021.

Abstract

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative pathogen of current COVID-19 pandemic, and insufficient production of type I interferon (IFN-I) is associated with the severe forms of the disease. Membrane (M) protein of SARS-CoV-2 has been reported to suppress host IFN-I production, but the underlying mechanism is not completely understood. In this study, SARS-CoV-2 M protein was confirmed to suppress the expression of IFNβ and interferon-stimulated genes induced by RIG-I, MDA5, IKKϵ, and TBK1, and to inhibit IRF3 phosphorylation and dimerization caused by TBK1. SARS-CoV-2 M could interact with MDA5, TRAF3, IKKϵ, and TBK1, and induce TBK1 degradation via K48-linked ubiquitination. The reduced TBK1 further impaired the formation of TRAF3-TANK-TBK1-IKKε complex that leads to inhibition of IFN-I production. Our study revealed a novel mechanism of SARS-CoV-2 M for negative regulation of IFN-I production, which would provide deeper insight into the innate immunosuppression and pathogenicity of SARS-CoV-2.

Keywords: SARS-CoV-2; TBK1; membrane protein; type I interferon; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DEAD Box Protein 58 / metabolism
  • HEK293 Cells
  • Humans
  • I-kappa B Kinase / metabolism
  • Interferon Regulatory Factor-3 / metabolism
  • Interferon Type I / biosynthesis*
  • Interferon-Induced Helicase, IFIH1 / metabolism
  • Protein Serine-Threonine Kinases / metabolism*
  • Proteolysis
  • Receptors, Immunologic / metabolism
  • SARS-CoV-2 / immunology*
  • Signal Transduction
  • TNF Receptor-Associated Factor 3 / metabolism
  • Ubiquitin / metabolism*
  • Viral Matrix Proteins / immunology*

Substances

  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • Receptors, Immunologic
  • TNF Receptor-Associated Factor 3
  • Ubiquitin
  • Viral Matrix Proteins
  • membrane protein, SARS-CoV-2
  • Protein Serine-Threonine Kinases
  • TBK1 protein, human
  • I-kappa B Kinase
  • RIGI protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • Interferon-Induced Helicase, IFIH1