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.

中文翻译：

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IL-17 受体信号体的系统分析揭示了强大的调节反馈回路。


IL-17 介导针对真菌和细菌的免疫保护，并促进自身免疫病理。然而，IL-17 受体（IL-17R）信号转导的调节仍然难以捉摸。我们开发了一种基于质谱的新型方法来识别 IL-17R 复合物的成分，然后使用反向遗传学分析它们的作用。除了将线性泛素链组装复合物 (LUBAC) 鉴定为 IL-17R 的重要信号转导成分之外，我们还确定 IL-17 信号传导受到 TBK1 和 IKKε 介导的强大负反馈环的调节。这些激酶通过磷酸化接头 ACT1 来终止 IL-17 信号传导，导致复合物中释放必需的泛素连接酶 TRAF6。 NEMO 将两种激酶募集至 IL-17R 复合物，证明 NEMO 在 IL-17 信号传导中具有前所未有的负面功能，与其在 NF-κB 激活中的作用不同。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。