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 IKK?. 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-?B activation. Our study provides a comprehensive view of the molecular events of the IL-17 signal transduction and its regulation.

SUBMITTER: Draberova H 

PROVIDER: S-EPMC7459424 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature