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Structural basis for IFN antagonism by human respiratory syncytial virus nonstructural protein 2 [Biochemistry]
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2021-03-09 , DOI: 10.1073/pnas.2020587118
Jingjing Pei 1 , Nicole D Wagner 2 , Angela J Zou 3 , Srirupa Chatterjee 1 , Dominika Borek 4 , Aidan R Cole 3 , Preston J Kim 3 , Christopher F Basler 5 , Zbyszek Otwinowski 4 , Michael L Gross 2 , Gaya K Amarasinghe 3 , Daisy W Leung 3, 6
Affiliation  

Human respiratory syncytial virus (RSV) nonstructural protein 2 (NS2) inhibits host interferon (IFN) responses stimulated by RSV infection by targeting early steps in the IFN-signaling pathway. But the molecular mechanisms related to how NS2 regulates these processes remain incompletely understood. To address this gap, here we solved the X-ray crystal structure of NS2. This structure revealed a unique fold that is distinct from other known viral IFN antagonists, including RSV NS1. We also show that NS2 directly interacts with an inactive conformation of the RIG-I–like receptors (RLRs) RIG-I and MDA5. NS2 binding prevents RLR ubiquitination, a process critical for prolonged activation of downstream signaling. Structural analysis, including by hydrogen-deuterium exchange coupled to mass spectrometry, revealed that the N terminus of NS2 is essential for binding to the RIG-I caspase activation and recruitment domains. N-terminal mutations significantly diminish RIG-I interactions and result in increased IFNβ messenger RNA levels. Collectively, our studies uncover a previously unappreciated regulatory mechanism by which NS2 further modulates host responses and define an approach for targeting host responses.



中文翻译:


人呼吸道合胞病毒非结构蛋白2拮抗干扰素的结构基础 [生物化学]



人呼吸道合胞病毒 (RSV) 非结构蛋白 2 (NS2) 通过靶向 IFN 信号通路的早期步骤,抑制 RSV 感染刺激的宿主干扰素 (IFN) 反应。但与 NS2 如何调节这些过程相关的分子机制仍不完全清楚。为了解决这个差距,我们在这里解决了 NS2 的 X 射线晶体结构。该结构揭示了与其他已知病毒 IFN 拮抗剂(包括 RSV NS1)不同的独特折叠。我们还表明 NS2 直接与 RIG-I 样受体 (RLR) RIG-I 和 MDA5 的非活性构象相互作用。 NS2 结合可防止 RLR 泛素化,这是延长下游信号传导的关键过程。结构分析(包括氢-氘交换与质谱联用)表明,NS2 的 N 末端对于结合 RIG-I caspase 激活和募集结构域至关重要。 N 端突变显着减少 RIG-I 相互作用并导致 IFNβ 信使 RNA 水平增加。总的来说,我们的研究揭示了一种以前未被重视的调节机制,NS2 通过该机制进一步调节宿主反应并定义了一种针对宿主反应的方法。

更新日期:2021-03-02
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