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线粒体抗病毒信号蛋白通过肿瘤坏死因子受体相关因子以依赖和不依赖核因子κB必需调节蛋白的方式激活TANK结合激酶1和IKKε。

MAVS activates TBK1 and IKKε through TRAFs in NEMO dependent and independent manner.

作者信息

Fang Run, Jiang Qifei, Zhou Xiang, Wang Chenguang, Guan Yukun, Tao Jianli, Xi Jianzhong, Feng Ji-Ming, Jiang Zhengfan

机构信息

Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, School of Life Sciences, Peking University, Beijing, China.

State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.

出版信息

PLoS Pathog. 2017 Nov 10;13(11):e1006720. doi: 10.1371/journal.ppat.1006720. eCollection 2017 Nov.

DOI:10.1371/journal.ppat.1006720
PMID:29125880
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5699845/
Abstract

Mitochondrial antiviral-signaling protein (MAVS) transmits signals from RIG-I-like receptors after RNA virus infections. However, the mechanism by which MAVS activates downstream components, such as TBK1 and IKKα/β, is unclear, although previous work suggests the involvement of NEMO or TBK1-binding proteins TANK, NAP1, and SINTBAD. Here, we report that MAVS-mediated innate immune activation is dependent on TRAFs, partially on NEMO, but not on TBK1-binding proteins. MAVS recruited TBK1/IKKε by TRAFs that were pre-associated with TBK1/IKKε via direct interaction between the coiled-coil domain of TRAFs and the SDD domain of TBK1/IKKε. TRAF2-/-3-/-5-/-6-/- cells completely lost RNA virus responses. TRAFs' E3 ligase activity was required for NEMO activation by synthesizing ubiquitin chains that bound to NEMO for NF-κB and TBK1/IKKε activation. NEMO-activated IKKα/β were important for TBK1/IKKε activation through IKKα/β-mediated TBK1/IKKε phosphorylation. Moreover, individual TRAFs differently mediated TBK1/IKKε activation and thus fine-tuned antiviral immunity under physiological conditions.

摘要

线粒体抗病毒信号蛋白（MAVS）在RNA病毒感染后传递来自视黄酸诱导基因I样受体的信号。然而，MAVS激活下游组分（如TBK1和IKKα/β）的机制尚不清楚，尽管先前的研究表明NEMO或TBK1结合蛋白TANK、NAP1和SINTBAD参与其中。在这里，我们报告MAVS介导的先天免疫激活依赖于肿瘤坏死因子受体相关因子（TRAFs），部分依赖于NEMO，但不依赖于TBK1结合蛋白。MAVS通过TRAFs招募TBK1/IKKε，这些TRAFs通过TRAFs的卷曲螺旋结构域与TBK1/IKKε的SDD结构域之间的直接相互作用而预先与TBK1/IKKε结合。TRAF2-/-3-/-5-/-6-/-细胞完全丧失了对RNA病毒的反应。TRAFs的E3连接酶活性通过合成与NEMO结合以激活NF-κB和TBK1/IKKε的泛素链来实现NEMO的激活。NEMO激活的IKKα/β通过IKKα/β介导的TBK1/IKKε磷酸化对TBK1/IKKε的激活很重要。此外，单个TRAFs以不同方式介导TBK1/IKKε的激活，从而在生理条件下微调抗病毒免疫。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/ae2831478cab/ppat.1006720.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/e0bbbab54df2/ppat.1006720.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/067a6a7f9bdb/ppat.1006720.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/002b21bbcfb7/ppat.1006720.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/b4ee33f96cc3/ppat.1006720.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/b209f679fd9f/ppat.1006720.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/4562a4301311/ppat.1006720.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/ae2831478cab/ppat.1006720.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/e0bbbab54df2/ppat.1006720.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/067a6a7f9bdb/ppat.1006720.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/002b21bbcfb7/ppat.1006720.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/b4ee33f96cc3/ppat.1006720.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/b209f679fd9f/ppat.1006720.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/4562a4301311/ppat.1006720.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4704/5699845/ae2831478cab/ppat.1006720.g007.jpg

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