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

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.