TDRD3 is an antiviral restriction factor that promotes IFN signaling with G3BP1.
TDRD3 is an antiviral restriction factor that promotes IFN signaling with G3BP1.
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DOI：
10.1371/journal.ppat.1010249
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发表时间：
2022-01
期刊：
影响因子：
6.7
通讯作者：
Lloyd RE
中科院分区：
文献类型：
--
作者：
Deater M;Tamhankar M;Lloyd RE
应激颗粒（SGs）是一种高度动态的细胞质灶，是在综合应激反应（ISR）激活时形成的，导致eIF2α磷酸化和全局翻译关闭。压力颗粒主要由G3BP1构成核，作为mRNA分类的中心，但越来越多的证据表明，它们也具有对细胞生存至关重要的细胞信号功能，特别是在病毒感染期间。我们之前的研究表明，SG的形成导致NFκB激活和JNK信号传导，这种关联可能部分归因于g3bp1依赖性的PKR向SGs募集。其他研究报道了G3BP1与1型干扰素信号系统（包括RIG-I）的各种先天免疫PRRs之间的密切关联。我们还报道了SG组装动力学取决于G3BP1的精氨酸甲基化状态。另一种快速定位于SGs的蛋白TDRD3是一种甲基解读蛋白，在细胞核内执行转录激活和接头功能，但其在SGs中的机制和功能尚不清楚。在这里，我们提供的证据表明，TDRD3部分基于G3BP1的甲基化电位定位于SGs。我们还表征了TDRD3在过表达过程中形成的颗粒，并表明这些颗粒可以在缺乏G3BP的情况下形成，但也包含在标准SGs中发现的翻译成分。我们还首次发现SGs可募集额外的干扰素效应物IRF3、IRF7、TBK1和Sting，并提供证据表明TDRD3可能在募集这些因子中发挥作用。我们还提出证据表明，TDRD3是一种新的抗病毒蛋白，可被肠病毒2A蛋白酶切割。细胞中G3BP1和TDRD3的敲低导致许多IFN效应物的转录调节发生改变，其复杂的调节模式是G3BP1和TDRD3所特有的。总之，我们描述了TDRD3在先天免疫中的新作用，其中G3BP1和TDRD3可能协同在先天抗病毒防御的调节中发挥重要作用。当细胞暴露于环境应激时，如氧化应激和病毒感染，它会诱导细胞反应，导致应激颗粒（SGs）的形成，该颗粒由停滞的翻译起始复合物（rna结合蛋白和mRNA）和许多其他细胞蛋白组成。当它们在病毒感染期间形成时，也被认为是抗病毒结构，但病毒可以阻止SG的形成以促进其生存，通常是通过靶向必需的SG蛋白G3BP1。在这里，我们发现甲基解读蛋白TDRD3部分基于G3BP1的甲基化电位定位于SGs，并可能在SGs的先天免疫因子募集中发挥作用。此外，当过表达时，TDRD3也可以独立于G3BP1形成sg样结构。我们也提出证据表明TDRD3是一种新的抗病毒蛋白。在缺乏TDRD3和G3BP1的情况下，病毒复制增强，病毒感染导致肠病毒蛋白酶2A切割TDRD3。最后，我们还表明，细胞中TDRD3和G3BP1的缺失导致许多IFN效应物在响应dsRNA时的转录激活受到限制。G3BP1和TDRD3的转录激活模式是不同的。我们得出结论，TDRD3可能在调节宿主抗病毒反应中发挥新的重要作用。
Stress granules (SGs) are highly dynamic cytoplasmic foci that form in response to activation of the integrated stress response (ISR) that results in eIF2α phosphorylation and global translation shutdown. Stress granules, which are largely nucleated by G3BP1, serve as hubs for mRNA triage, but there is mounting evidence that they also perform cell signaling functions that are vital to cell survival, particularly during viral infection. We previously showed that SG formation leads to NFκB activation and JNK signaling and that this association may be due in part to G3BP1-dependent recruitment of PKR to SGs. Others have reported close associations between G3BP1 and various innate immune PRRs of the type 1 interferon signaling system, including RIG-I. We also reported SG assembly dynamics is dependent on the arginine-methylation status of G3BP1. Another protein that rapidly localizes to SGs, TDRD3, is a methyl reader protein that performs transcriptional activation and adaptor functions within the nucleus, but neither the mechanism nor its function in SGs is clear. Here, we present evidence that TDRD3 localizes to SGs partly based upon methylation potential of G3BP1. We also characterize granules that TDRD3 forms during overexpression and show that these granules can form in the absence of G3BP but also contain translation components found in canonical SGs. We also show for the first time that SGs recruit additional interferon effectors IRF3, IRF7, TBK1, and Sting, and provide evidence that TDRD3 may play a role in recruitment of these factors. We also present evidence that TDRD3 is a novel antiviral protein that is cleaved by enteroviral 2A proteinase. G3BP1 and TDRD3 knockdown in cells results in altered transcriptional regulation of numerous IFN effectors in complex modulatory patterns that are distinctive for G3BP1 and TDRD3. Overall, we describe a novel role of TDRD3 in innate immunity in which G3BP1 and TDRD3 may coordinate to play important roles in regulation of innate antiviral defenses. When cells are exposed to environmental stresses, such as oxidative stress and viral infection, it induces a cellular response leading to the formation of Stress Granules (SGs) composed of stalled translation initiation complexes (RNA-binding proteins and mRNA) and many other cellular proteins. SGs are also considered to be antiviral structures when they form during viral infection, but viruses can block SG formation to facilitate their survival, often by targeting the essential SG protein G3BP1. Here, we show that a methyl reader protein, TDRD3, localizes to SGs partly based on the methylation potential of G3BP1, and may play a role in the recruitment of innate immune factors to SGs. Further, when overexpressed, TDRD3 can also form SG-like structures independently of G3BP1. We also present evidence that TDRD3 is a novel antiviral protein. Virus replication is enhanced in the absence of both TDRD3 and G3BP1, and virus infection leads to cleavage of TDRD3 by the enterovirus proteinase 2A. Finally, we also show that depletion of TDRD3 and G3BP1 together in cells leads to restriction of transcriptional activation of numerous IFN effectors in response to dsRNA. The patterns of transcriptional activation are distinctive for G3BP1 and TDRD3. We conclude that TDRD3 may play a novel and important role in the regulation of the host antiviral response.
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TDRD3是一种新型的都铎式结构域的蛋白质，将其定位于细胞质应激颗粒。
影响因子：
3.5
作者：
Goulet, Isabelle;Boisvenue, Sophie;Mokas, Sophie;Mazroui, Rachid;Cote, Jocelyn
通讯作者：
Cote, Jocelyn
影响因子：
9.8
作者：
McQuin C;Goodman A;Chernyshev V;Kamentsky L;Cimini BA;Karhohs KW;Doan M;Ding L;Rafelski SM;Thirstrup D;Wiegraebe W;Singh S;Becker T;Caicedo JC;Carpenter AE
通讯作者：
Carpenter AE
DOI：
10.4049/jimmunol.0903563
发表时间：
2010-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Akhtar LN;Qin H;Muldowney MT;Yanagisawa LL;Kutsch O;Clements JE;Benveniste EN
通讯作者：
Benveniste EN
影响因子：
3.7
作者：
Onomoto K;Jogi M;Yoo JS;Narita R;Morimoto S;Takemura A;Sambhara S;Kawaguchi A;Osari S;Nagata K;Matsumiya T;Namiki H;Yoneyama M;Fujita T
通讯作者：
Fujita T
影响因子：
19
作者：
Protter DSW;Parker R
通讯作者：
Parker R