Department of Pediatric Emergency, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
State Key Laboratory of Virology and National Virus Resource Center, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China.
J Med Virol. 2023 Jun;95(6):e28881. doi: 10.1002/jmv.28881.
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an unprecedented threat to human health since late 2019. Notably, the progression of the disease is associated with impaired antiviral interferon (IFN) responses. Although multiple viral proteins were identified as potential IFN antagonists, the underlying molecular mechanisms remain to be fully elucidated. In this study, we firstly demonstrate that SARS-CoV-2 NSP13 protein robustly antagonizes IFN response induced by the constitutively active form of transcription factor IRF3 (IRF3/5D). This induction of IFN response by IRF3/5D is independent of the upstream kinase, TBK1, a previously reported NSP13 target, thus indicating that NSP13 can act at the level of IRF3 to antagonize IFN production. Consistently, NSP13 exhibits a specific, TBK1-independent interaction with IRF3, which, moreover, is much stronger than that of NSP13 with TBK1. Furthermore, the NSP13-IRF3 interaction was shown to occur between the NSP13 1B domain and IRF3 IRF association domain (IAD). In agreement with the strong targeting of IRF3 by NSP13, we then found that NSP13 blocks IRF3-directed signal transduction and antiviral gene expression, counteracting IRF3-driven anti-SARS-CoV-2 activity. These data suggest that IRF3 is likely to be a major target of NSP13 in antagonizing antiviral IFN responses and provide new insights into the SARS-CoV-2-host interactions that lead to viral immune evasion.
2019 年冠状病毒病（COVID-19），由严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）引起，自 2019 年末以来对人类健康构成了前所未有的威胁。值得注意的是，疾病的进展与抗病毒干扰素（IFN）反应受损有关。尽管已经鉴定出多种病毒蛋白作为潜在的 IFN 拮抗剂，但潜在的分子机制仍有待充分阐明。在这项研究中，我们首先证明 SARS-CoV-2 NSP13 蛋白强烈拮抗由转录因子 IRF3（IRF3/5D）组成激活形式诱导的 IFN 反应。IRF3/5D 诱导的 IFN 反应独立于上游激酶 TBK1，这是先前报道的 NSP13 靶标，因此表明 NSP13 可以在 IRF3 水平上发挥作用拮抗 IFN 产生。一致地，NSP13 与 IRF3 表现出特异性、TBK1 非依赖性相互作用，而且，其与 TBK1 的相互作用要强得多。此外，还表明 NSP13-IRF3 相互作用发生在 NSP13 的 1B 结构域和 IRF3 IRF 结合结构域（IAD）之间。与 NSP13 对 IRF3 的强烈靶向作用一致，我们发现 NSP13 阻断了 IRF3 介导的信号转导和抗病毒基因表达，从而抵消了 IRF3 驱动的抗 SARS-CoV-2 活性。这些数据表明，IRF3 可能是 NSP13 拮抗抗病毒 IFN 反应的主要靶标，并为导致病毒免疫逃避的 SARS-CoV-2-宿主相互作用提供了新的见解。
