Encephalomyocarditis Virus Disrupts Stress Granules, the Critical Platform for Triggering Antiviral Innate Immune Responses
Encephalomyocarditis Virus Disrupts Stress Granules, the Critical Platform for Triggering Antiviral Innate Immune Responses
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DOI：
10.1128/jvi.03248-12
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发表时间：
2013-09-01
影响因子：
5.4
通讯作者：
Fujita, Takashi
中科院分区：
文献类型：
--
作者：
Ng, Chen Seng;Jogi, Michihiko;Fujita, Takashi
在应激反应中，细胞诱导核糖核蛋白聚集体，称为应激颗粒（SG）。SG是含有停滞mRNA的瞬时位点，其最终被降解或回收用于翻译。一些病毒的感染，包括缺失非结构蛋白1（IAV Delta NS 1）的甲型流感病毒，诱导SG样蛋白聚集体。以前，我们表明，IAV Delta NS 1诱导的SG是有效诱导I型干扰素（IFN）所必需的。在这里，我们研究了SG形成不同的病毒使用绿色荧光蛋白（GFP）标记的Ras-间隙SH 3结构域结合蛋白1（GFP-G3 BP 1）作为SG探针。用不同的病毒感染稳定表达GFP-G3 BP 1的HeLa细胞，并用延时显微镜实时监测GFP荧光。不同病毒的SG形成分为4种不同的模式：无SG形成、稳定SG形成、瞬时SG形成和交替SG形成。我们集中在脑心肌炎病毒（EMCV）感染，表现出短暂的SG形成。我们发现EMCV通过与脊髓灰质炎病毒相似的机制，在感染晚期（>8小时）通过切割G3 BP 1破坏SG。对切割具有抗性的G3 BP 1突变体的表达赋予了SGs的持续形成以及在感染的晚期阶段增强的IFN和其他细胞因子的诱导。此外，内源性G3 BP 1的敲低阻断了SG的形成，减弱了IFN的诱导并增强了病毒复制。总之，我们的研究结果表明，SGs作为抗病毒平台的关键作用，并阐明了病毒干扰宿主应激和随后的抗病毒反应的机制之一。
In response to stress, cells induce ribonucleoprotein aggregates, termed stress granules (SGs). SGs are transient loci containing translation-stalled mRNA, which is eventually degraded or recycled for translation. Infection of some viruses, including influenza A virus with a deletion of nonstructural protein 1 (IAV Delta NS1), induces SG-like protein aggregates. Previously, we showed that IAV Delta NS1-induced SGs are required for efficient induction of type I interferon (IFN). Here, we investigated SG formation by different viruses using green fluorescent protein (GFP)-tagged Ras-Gap SH3 domain binding protein 1 (GFP-G3BP1) as an SG probe. HeLa cells stably expressing GFP-G3BP1 were infected with different viruses, and GFP fluorescence was monitored live with time-lapse microscopy. SG formations by different viruses was classified into 4 different patterns: no SG formation, stable SG formation, transient SG formation, and alternate SG formation. We focused on encephalomyocarditis virus (EMCV) infection, which exhibited transient SG formation. We found that EMCV disrupts SGs by cleavage of G3BP1 at late stages of infection (>8 h) through a mechanism similar to that used by poliovirus. Expression of a G3BP1 mutant that is resistant to the cleavage conferred persistent formation of SGs as well as an enhanced induction of IFN and other cytokines at late stages of infection. Additionally, knockdown of endogenous G3BP1 blocked SG formation with an attenuated induction of IFN and potentiated viral replication. Taken together, our findings suggest a critical role of SGs as an antiviral platform and shed light on one of the mechanisms by which a virus interferes with host stress and subsequent antiviral responses.