Structures of arenaviral nucleoproteins with triphosphate dsRNA reveal a unique mechanism of immune suppression.
Structures of arenaviral nucleoproteins with triphosphate dsRNA reveal a unique mechanism of immune suppression.
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DOI：
10.1074/jbc.m112.420521
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发表时间：
2013-06-07
期刊：
影响因子：
--
通讯作者：
Dong C
中科院分区：
文献类型：
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作者：
Jiang X;Huang Q;Wang W;Dong H;Ly H;Liang Y;Dong C
背景：沙粒病毒核蛋白在先天免疫抑制中起关键作用。结果：确定了Lassa核蛋白与三磷酸dsRNA和Tacaribe病毒核蛋白复合物的结构。结论：Lassa和Tacaribe核蛋白均能通过降解免疫刺激性dsRNA而强烈抑制IFN-β的产生。意义：揭示了沙粒病毒核蛋白独特的免疫抑制模式。严重拉沙热的一个标志是全身免疫抑制，其机制知之甚少。拉沙病毒（LASV）核蛋白（NP）是目前已知的唯一一种3′-5′核糖核酸外切酶，它可能通过降解免疫刺激RNA来抑制I型干扰素（IFN）的产生。LASV NP的这种独特的酶活性如何识别和处理RNA底物尚不清楚。我们提供了一个具有催化活性的外切核糖核酸酶结构域的LASV NP（LASV NP-C）在降解5′三磷酸双链（ds）RNA底物，一个典型的病原体相关的分子模式分子，诱导I型IFN的生产过程中的原子视图。此外，我们首次提供了塔卡里布沙粒病毒（TCRV）NP的活性核糖核酸外切酶结构域的高分辨率晶体结构。再加上在体外酶和细胞为基础的干扰素抑制试验，这些结构分析有力地支持了一个统一的模型，所有已知的沙粒病毒共享的核糖核酸酶依赖的IFN抑制机制。从这些研究中学到的新知识应该有助于开发针对致病性沙粒病毒的治疗方法，这些病毒每年可以感染数十万人并杀死数千人。
Background: Arenaviral nucleoproteins play a critical role in innate immune suppression. Results: Structures of Lassa nucleoprotein in complex with triphosphate dsRNA and Tacaribe virus nucleoprotein have been determined. Conclusion: Both Lassa and Tacaribe nucleoproteins can strongly inhibit IFN-β production by degrading immune-stimulatory dsRNA. Significance: A unique immune suppression mode of arenaviral nucleoproteins has been revealed. A hallmark of severe Lassa fever is the generalized immune suppression, the mechanism of which is poorly understood. Lassa virus (LASV) nucleoprotein (NP) is the only known 3′-5′ exoribonuclease that can suppress type I interferon (IFN) production possibly by degrading immune-stimulatory RNAs. How this unique enzymatic activity of LASV NP recognizes and processes RNA substrates is unknown. We provide an atomic view of a catalytically active exoribonuclease domain of LASV NP (LASV NP-C) in the process of degrading a 5′ triphosphate double-stranded (ds) RNA substrate, a typical pathogen-associated molecular pattern molecule, to induce type I IFN production. Additionally, we provide for the first time a high-resolution crystal structure of an active exoribonuclease domain of Tacaribe arenavirus (TCRV) NP. Coupled with the in vitro enzymatic and cell-based interferon suppression assays, these structural analyses strongly support a unified model of an exoribonuclease-dependent IFN suppression mechanism shared by all known arenaviruses. New knowledge learned from these studies should aid the development of therapeutics against pathogenic arenaviruses that can infect hundreds of thousands of individuals and kill thousands annually.