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.

Department of Haematooncology University Hospital Ostrava Ostrava Czech Republic

Faculty of Medicine University of Ostrava Ostrava Czech Republic

Institute of Quantitative Biology Biochemistry and Biotechnology SynthSys School of Biological Sciences University of Edinburgh Edinburgh UK

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

Laboratory of Immunity and Cell Communication BIOCEV 1st Faculty of Medicine Charles University Vestec Czech Republic

Laboratory of Mass Spectrometry BIOCEV Faculty of Science Charles University Prague Czech Republic

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RefSeq
PXD019020

GEO
GSE150410