SARS-CoV-2 Membrane Protein Inhibits Type I Interferon Production Through Ubiquitin-Mediated Degradation of TBK1.
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 IFN? and interferon-stimulated genes induced by RIG-I, MDA5, IKK?, and TBK1, and to inhibit IRF3 phosphorylation and dimerization caused by TBK1. SARS-CoV-2 M could interact with MDA5, TRAF3, IKK?, and TBK1, and induce TBK1 degradation via K48-linked ubiquitination. The reduced TBK1 further impaired the formation of TRAF3-TANK-TBK1-IKK? 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.
Mesh Terms:
DEAD Box Protein 58, HEK293 Cells, Humans, I-kappa B Kinase, Interferon Regulatory Factor-3, Interferon Type I, Interferon-Induced Helicase, IFIH1, Protein-Serine-Threonine Kinases, Proteolysis, Receptors, Immunologic, SARS-CoV-2, Signal Transduction, TNF Receptor-Associated Factor 3, Ubiquitin, Viral Matrix Proteins
DEAD Box Protein 58, HEK293 Cells, Humans, I-kappa B Kinase, Interferon Regulatory Factor-3, Interferon Type I, Interferon-Induced Helicase, IFIH1, Protein-Serine-Threonine Kinases, Proteolysis, Receptors, Immunologic, SARS-CoV-2, Signal Transduction, TNF Receptor-Associated Factor 3, Ubiquitin, Viral Matrix Proteins
Front Immunol
Date: Jun. 05, 2021
PubMed ID: 34084167
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