title: Interleukin-17F signaling requires ubiquitination of interleukin-17 receptor via TRAF6.
abstract: Interleukin-17F (IL-17F), together with interleukin-17A (IL-17 or IL-17A), is a marker of T(H)17 cells, a new lineage of effector CD4(+) T cells to contribute to pathogenesis of a growing list of autoimmune and inflammatory diseases, such as experimental autoimmune encephalitis (EAE) and collagen-induced arthritis (CIA). IL-17F, similar to IL-17A, was reported to employ interleukin-17 receptor (IL-17R or IL-17RA) for signaling but the downstream cascades remain largely elusive. Here we report that TRAF6 interacts with IL-17R and mediates ubiquitination of the receptor. We observed that IL-17F and IL-17A could induce IL-17R ubiquitination and DN-TRAF6, a dominant-negative mutant, could block IL-17F- but not IL-17A-triggered ubiquitination of IL-17R. Moreover, we showed that the ubiquitination of IL-17R was positively correlated with the downstream signaling, as evaluated by a luciferase reporter driven by a putative native promoter of 24p3, an IL-17 targeted gene. Our results indicate that ubiquitination of IL-17R mediated by TRAF6 plays a critical role in IL-17F signaling. This study, for the first time, reveals a possible molecular mechanism that the initiation of the IL-17F/IL-17R signaling pathway requires the receptor ubiquitination by TRAF6.
authors.affiliation: Department of Biological Sciences and Biotechnology, School of Medicine, Institute of Biomedicine, State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University, Beijing 100084, China.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Rong
authors.forename: Long
authors.initials: L
authors.lastname: Cheng
authors.forename: Yongming
authors.initials: Y
authors.lastname: Ren
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Li
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Li
authors.forename: Xueni
authors.initials: X
authors.lastname: Li
authors.forename: Hongge
authors.initials: H
authors.lastname: Li
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Fu
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Chang
mesh_terms: D000818:Animals; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D051379:Mice; D053722:Receptors, Interleukin-17 / Q000378:metabolism*; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C109985:IL17RA protein, human; D020381:Interleukin-17; D053722:Receptors, Interleukin-17; D048029:TNF Receptor-Associated Factor 6; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases