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The mechanism of RNA capping by SARS-CoV-2
Nature ( IF 64.8 ) Pub Date : 2022-08-09 , DOI: 10.1038/s41586-022-05185-z
Gina J Park 1 , Adam Osinski 1 , Genaro Hernandez 1 , Jennifer L Eitson 2 , Abir Majumdar 1 , Marco Tonelli 3 , Katie Henzler-Wildman 3 , Krzysztof Pawłowski 1, 4, 5 , Zhe Chen 6 , Yang Li 6 , John W Schoggins 2 , Vincent S Tagliabracci 1, 7, 8, 9
Affiliation  

The SARS-CoV-2 RNA genome contains a 5′-cap that facilitates translation of viral proteins, protection from exonucleases and evasion of the host immune response1-4. How this cap is made in SARS-CoV-2 is not completely understood. Here, we reconstitute the SARS-CoV-2 7MeGpppA2′-O-Me-RNA cap using virally encoded non-structural proteins (nsps). We show that the kinase-like NiRAN domain5 of nsp12 transfers RNA to the amino terminus of nsp9, forming a covalent RNA-protein intermediate (a process termed RNAylation). Subsequently, the NiRAN domain transfers RNA to GDP, forming the core cap structure GpppA-RNA. The nsp146 and nsp167 methyltransferases then add methyl groups to form functional cap structures. Structural analyses of the replication-transcription complex bound to nsp9 identified key interactions that mediate the capping reaction. Furthermore, we demonstrate in a reverse genetics system8 that the N-terminus of nsp9 and the kinase-like active site residues in the NiRAN domain are required for successful SARS-CoV-2 replication. Collectively, our results reveal an unconventional mechanism by which SARS-CoV-2 caps its RNA genome, thus exposing a new target in the development of antivirals to treat COVID-19.



中文翻译:

SARS-CoV-2 的 RNA 加帽机制

SARS-CoV-2 RNA 基因组包含一个 5'-帽,可促进病毒蛋白的翻译、防止外切核酸酶和逃避宿主免疫反应1-4。这个帽子是如何在 SARS-CoV-2 中制成的尚不完全清楚。在这里,我们使用病毒编码的非结构蛋白 (nsps)重构 SARS-CoV-2 7Me GpppA 2'-O-Me -RNA 帽。我们显示 nsp12 的激酶样 NiRAN 结构域5将 RNA 转移到 nsp9 的氨基末端,形成共价 RNA-蛋白质中间体(称为 RNA 化的过程)。随后,NiRAN 结构域将 RNA 转移到 GDP,形成核心帽结构 GpppA-RNA。nsp14 6和 nsp16 7然后甲基转移酶添加甲基以形成功能性帽结构。与 nsp9 结合的复制转录复合物的结构分析确定了介导加帽反应的关键相互作用。此外,我们在反向遗传学系统8中证明,成功复制 SARS-CoV-2 需要 nsp9 的 N 末端和 NiRAN 结构域中的激酶样活性位点残基。总的来说,我们的研究结果揭示了 SARS-CoV-2 为其 RNA 基因组加帽的非常规机制,从而揭示了开发治疗 COVID-19 的抗病毒药物的新靶点。

更新日期:2022-08-09
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