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系统分析 IL-17 受体信号转导复合物揭示了一个强大的负反馈调节环。

Systematic analysis of the IL-17 receptor signalosome reveals a robust regulatory feedback loop.

机构信息

Laboratory of Immunity & Cell Communication, BIOCEV, First Faculty of Medicine, Charles University, Vestec, Czech Republic.

Laboratory of Adaptive Immunity, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.

出版信息

EMBO J. 2020 Sep 1;39(17):e104202. doi: 10.15252/embj.2019104202. Epub 2020 Jul 21.

DOI:10.15252/embj.2019104202
PMID:32696476
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7459424/
Abstract

IL-17 mediates immune protection from fungi and bacteria, as well as it promotes autoimmune pathologies. However, the regulation of the signal transduction from the IL-17 receptor (IL-17R) remained elusive. We developed a novel mass spectrometry-based approach to identify components of the IL-17R complex followed by analysis of their roles using reverse genetics. Besides the identification of linear ubiquitin chain assembly complex (LUBAC) as an important signal transducing component of IL-17R, we established that IL-17 signaling is regulated by a robust negative feedback loop mediated by TBK1 and IKKε. These kinases terminate IL-17 signaling by phosphorylating the adaptor ACT1 leading to the release of the essential ubiquitin ligase TRAF6 from the complex. NEMO recruits both kinases to the IL-17R complex, documenting that NEMO has an unprecedented negative function in IL-17 signaling, distinct from its role in NF-κB activation. Our study provides a comprehensive view of the molecular events of the IL-17 signal transduction and its regulation.

摘要

IL-17 介导了对真菌和细菌的免疫保护，同时也促进了自身免疫性疾病。然而，IL-17 受体（IL-17R）的信号转导调控仍然难以捉摸。我们开发了一种新的基于质谱的方法来鉴定 IL-17R 复合物的组成部分，然后使用反向遗传学分析它们的作用。除了鉴定线性泛素链组装复合物（LUBAC）作为 IL-17R 的重要信号转导成分外，我们还确立了 IL-17 信号受 TBK1 和 IKKε 介导的强大负反馈环调控。这些激酶通过磷酸化衔接蛋白 ACT1 终止 IL-17 信号，导致必需的泛素连接酶 TRAF6 从复合物中释放。NEMO 将这两种激酶募集到 IL-17R 复合物上，证明了 NEMO 在 IL-17 信号中的作用与 NF-κB 激活中的作用不同，具有前所未有的负调节功能。我们的研究提供了 IL-17 信号转导及其调控的分子事件的全面视图。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/99fe2925d6a3/EMBJ-39-e104202-g014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/4c60a49abdba/EMBJ-39-e104202-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/d55bbebbf4aa/EMBJ-39-e104202-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/f906ebf5821b/EMBJ-39-e104202-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/aa1f581230a7/EMBJ-39-e104202-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/22b61d582202/EMBJ-39-e104202-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/f67c27267c15/EMBJ-39-e104202-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/6a44e2a5c51f/EMBJ-39-e104202-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/0f303d49aa14/EMBJ-39-e104202-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/71ad4c9318a0/EMBJ-39-e104202-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/4d6903e0a03d/EMBJ-39-e104202-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/35e2919c1aaa/EMBJ-39-e104202-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/a5d5773b4335/EMBJ-39-e104202-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/99fe2925d6a3/EMBJ-39-e104202-g014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/4c60a49abdba/EMBJ-39-e104202-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/d55bbebbf4aa/EMBJ-39-e104202-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/f906ebf5821b/EMBJ-39-e104202-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/aa1f581230a7/EMBJ-39-e104202-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/22b61d582202/EMBJ-39-e104202-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/f67c27267c15/EMBJ-39-e104202-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/6a44e2a5c51f/EMBJ-39-e104202-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/0f303d49aa14/EMBJ-39-e104202-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/71ad4c9318a0/EMBJ-39-e104202-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/4d6903e0a03d/EMBJ-39-e104202-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/35e2919c1aaa/EMBJ-39-e104202-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/a5d5773b4335/EMBJ-39-e104202-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0dfb/7459424/99fe2925d6a3/EMBJ-39-e104202-g014.jpg

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