adapter protein; cutting edge; gene activation; IKK epsilon; ikk-epsilon; il-17; kappa-b kinase; linear ubiquitin; lubac; messenger-rna; nemo; poly-ubiquitin chains; signaling complex; tank-binding kinase-1; tbk1

IL-17 mediates immune protection from fungi and bacteria, as well as it promotes autoimmune pathologies. However, the regulation of the signal transduction from theIL-17 receptor (IL-17R) remained elusive. We developed a novel mass spectrometry-based approach to identify components of theIL-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 ofIL-17R, we established thatIL-17 signaling is regulated by a robust negative feedback loop mediated byTBK1 andIKK epsilon. These kinases terminateIL-17 signaling by phosphorylating the adaptorACT1 leading to the release of the essential ubiquitin ligaseTRAF6 from the complex.NEMOrecruits both kinases to theIL-17R complex, documenting thatNEMOhas an unprecedented negative function inIL-17 signaling, distinct from its role inNF-kappa B activation. Our study provides a comprehensive view of the molecular events of theIL-17 signal transduction and its regulation.