Translational shutdown and evasion of the innate immune response by SARS-CoV-2 NSP14 protein.
Translational shutdown and evasion of the innate immune response by SARS-CoV-2 NSP14 protein.
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DOI：
10.1073/pnas.2101161118
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发表时间：
2021-06-15
影响因子：
11.1
通讯作者：
Cresswell P
中科院分区：
文献类型：
--
作者：
Hsu JC;Laurent-Rolle M;Pawlak JB;Wilen CB;Cresswell P
为了建立感染，致病性病毒必须克服I型干扰素（IFN-I）抗病毒应答。先前的一项研究表明，SARS-CoV-2 NSP 14能够抑制IFN-I反应。在这项研究中，我们报告，SARS-CoV-2 NSP 14是一种病毒编码的翻译抑制因子，它关闭宿主蛋白质合成，包括抗病毒蛋白的合成。我们的发现揭示了SARS-CoV-2逃避宿主抗病毒反应的机制。全面了解SARS-CoV-2破坏宿主免疫反应的策略对于设计下一代抗病毒药物和为未来出现的病毒病原体做准备至关重要。持续的COVID-19大流行导致了前所未有的全球健康危机。严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）是COVID-19的病原体。破坏宿主蛋白质合成是致病病毒在宿主中复制和繁殖的常见策略。在这项研究中，我们表明，SARS-CoV-2能够关闭宿主蛋白质的合成和SARS-CoV-2非结构蛋白NSP 14发挥这种活性。我们发现NSP 14的翻译抑制活性在人类冠状病毒中是保守的。NSP 14通过其核糖核酸外切酶（ExoN）和N7-甲基转移酶（N7-MTase）活性的贡献而为病毒复制所需。SARS-CoV-2 NSP 14的ExoN或N7-MTase活性位点的突变消除了其翻译抑制活性。此外，我们发现NSP 14 − NSP 10复合物的形成增强了NSP 14执行的翻译抑制。因此，NSP 14的翻译关闭消除了干扰素刺激基因（ISG）的I型干扰素（IFN-I）依赖性诱导。总之，我们发现SARS-CoV-2通过翻译抑制剂关闭宿主先天免疫反应，为SARS-CoV-2的发病机制提供了见解。
To establish infection, pathogenic viruses have to overcome the type I interferon (IFN-I) antiviral response. A previous study demonstrated that the SARS-CoV-2 NSP14 is able to inhibit IFN-I responses. In this study, we report that SARS-CoV-2 NSP14 is a virus-encoded translation inhibitory factor which shuts down host protein synthesis, including synthesis of antiviral proteins. Our finding reveals a mechanism by which SARS-CoV-2 evades host antiviral responses. A comprehensive understanding of the strategies employed by SARS-CoV-2 to subvert host immune responses is critical for the design of next-generation antivirals and to prepare for future emerging viral pathogens. The ongoing COVID-19 pandemic has caused an unprecedented global health crisis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19. Subversion of host protein synthesis is a common strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to shut down host protein synthesis and that SARS-CoV-2 nonstructural protein NSP14 exerts this activity. We show that the translation inhibition activity of NSP14 is conserved in human coronaviruses. NSP14 is required for virus replication through contribution of its exoribonuclease (ExoN) and N7-methyltransferase (N7-MTase) activities. Mutations in the ExoN or N7-MTase active sites of SARS-CoV-2 NSP14 abolish its translation inhibition activity. In addition, we show that the formation of NSP14−NSP10 complex enhances translation inhibition executed by NSP14. Consequently, the translational shutdown by NSP14 abolishes the type I interferon (IFN-I)-dependent induction of interferon-stimulated genes (ISGs). Together, we find that SARS-CoV-2 shuts down host innate immune responses via a translation inhibitor, providing insights into the pathogenesis of SARS-CoV-2.
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