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.

中文翻译：

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SARS-CoV-2 Nsp8 通过损害 TRIM4 介导的 K63 连接的多聚泛素化来抑制 MDA5 抗病毒免疫反应。

黑色素瘤分化相关基因 5 (MDA5) 作为细胞质 RNA 传感器来检测病毒 dsRNA，并介导针对 RNA 病毒感染的抗病毒先天免疫反应。识别病毒 dsRNA 后，MDA5 被 K63 连接的多聚泛素化激活，然后触发 MAVS 的募集以及 TBK1 和 IKKα/β 的激活，随后导致 IRF3 和 NF-κB 磷酸化。然而，用于 MDA5 K63 多聚泛素化的特异性 E3 泛素连接酶尚未得到很好的表征。大量有症状和严重的 SARS-CoV-2 感染正在全球范围内蔓延，I 型干扰素和抗病毒免疫药物治疗效果不佳表明 SARS-CoV-2 通过几种未知机制逃避抗病毒免疫反应。在此，我们报告 SARS-CoV-2 非结构蛋白 8 (nsp8) 充当抗病毒先天免疫和炎症反应的抑制剂，从而促进 SARS-CoV-2 的感染。它通过与 MDA5 和 TRIM4 结合并削弱 TRIM4 介导的 MDA5 K63 连接的多聚泛素化来下调 I 型干扰素、IFN 刺激基因和促炎细胞因子的表达。我们的研究结果表明，nsp8 在 SARS-CoV-2 感染期间介导先天免疫逃避，并可能作为未来 SARS-CoV-2 传染病治疗的潜在靶点。