SARS-CoV-2 Nsp8 suppresses MDA5 antiviral immune responses by impairing TRIM4-mediated K63-linked polyubiquitination

• Published in: PLoS pathogens 2023-11, Vol.19 (11), p.e1011792-e1011792
• Main Authors: Zhang, Xiaolin, Yang, Ziwei, Pan, Ting, Sun, Qinqin, Chen, Qingyang, Wang, Pei-Hui, Li, Xiaojuan, Kuang, Ersheng
• Format: Article
• Language: English
• Subjects: Analysis; Antiviral drugs; Biological response modifiers; COVID-19; Cytokines; Disease susceptibility; Double-stranded RNA; Drug discovery; Gene expression; Health aspects; Immune response; Infection; Infections; Infectious diseases; Inflammation; Innate immunity; Interferon; Interferon regulatory factor 3; Melanoma; Methods; NF-κB protein; Pathogenesis; Phosphorylation; Plasmids; Proteins; Ribonucleic acid; RNA; RNA viruses; Severe acute respiratory syndrome coronavirus 2; Ubiquitin-proteasome system; Ubiquitin-protein ligase; Viral diseases
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011792

Melanoma differentiation-associated gene-5 (MDA5) acts as a cytoplasmic RNA sensor to detect viral dsRNA and mediates antiviral innate immune responses to infection by RNA viruses. Upon recognition of viral dsRNA, MDA5 is activated with K63-linked polyubiquitination and then triggers the recruitment of MAVS and activation of TBK1 and IKKα/β, subsequently leading to IRF3 and NF-κB phosphorylation. However, the specific E3 ubiquitin ligase for MDA5 K63-polyubiquitination has not been well characterized. Great numbers of symptomatic and severe infections of SARS-CoV-2 are spreading worldwide, and the poor efficacy of treatment with type I interferon and antiviral immune agents indicates that SARS-CoV-2 escapes from antiviral immune responses via several unknown mechanisms. Here, we report that SARS-CoV-2 nonstructural protein 8 (nsp8) acts as a suppressor of antiviral innate immune and inflammatory responses to promote infection of SARS-CoV-2. It downregulates the expression of type I interferon, IFN-stimulated genes and proinflammatory cytokines by binding to MDA5 and TRIM4 and impairing TRIM4-mediated MDA5 K63-linked polyubiquitination. Our findings reveal that nsp8 mediates innate immune evasion during SARS-CoV-2 infection and may serve as a potential target for future therapeutics for SARS-CoV-2 infectious diseases.