IL-17-induced NF-κB Activation via CIKS/Act1

• Published in: The Journal of biological chemistry Vol. 286; no. 15; pp. 12881 - 12890
• Main Authors: Sønder, Søren Ulrik, Saret, Sun, Tang, Wanhu, Sturdevant, Dan E., Porcella, Stephen F., Siebenlist, Ulrich
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 15-04-2011
• Subjects: CIKS; Cytokine; Gene Expression; Interleukin 17; NF-κB Transcription Factor; Signal Transduction; TRAF6; Tumor Necrosis Factor (TNF); CIKS; Gene Expression; Signal Transduction; TRAF6; Cytokine; NF-κB Transcription Factor; Tumor Necrosis Factor (TNF); Interleukin 17
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M110.199547

Interleukin-17 (IL-17) is essential in host defense against extracellular bacteria and fungi, especially at mucosal sites, but it also contributes significantly to inflammatory and autoimmune disease pathologies. Binding of IL-17 to its receptor leads to recruitment of adaptor protein CIKS/Act1 via heterotypic association of their respective SEFIR domains and activation of transcription factor NF-κB; it is not known whether CIKS and/or NF-κB are required for all gene induction events. Here we report that CIKS is essential for all IL-17-induced immediate-early genes in primary mouse embryo fibroblasts, whereas NF-κB is profoundly involved. We also identify a novel subdomain in the N terminus of CIKS that is essential for IL-17-mediated NF-κB activation. This domain is both necessary and sufficient for interaction between CIKS and TRAF6, an adaptor required for NF-κB activation. The ability of decoy peptides to block this interaction may provide a new therapeutic strategy for intervention in IL-17-driven autoimmune and inflammatory diseases.