title: Negative regulation of IL-17-mediated signaling and inflammation by the ubiquitin-specific protease USP25.
abstract: Interleukin 17 (IL-17) is important in infection and autoimmunity; how it signals remains poorly understood. In this study, we identified the ubiquitin-specific protease USP25 as a negative regulator of IL-17-mediated signaling and inflammation. Overexpression of USP25 inhibited IL-17-triggered signaling, whereas USP25 deficiency resulted in more phosphorylation of the inhibitor IκBα and kinase Jnk and higher expression of chemokines and cytokines, as well as a prolonged half-life for chemokine CXCL1-encoding mRNA after treatment with IL-17. Consistent with that, Usp25(-/-) mice showed greater sensitivity to IL-17-dependent inflammation and autoimmunity in vivo. Mechanistically, stimulation with IL-17 induced the association of USP25 with the adaptors TRAF5 and TRAF6, and USP25 induced removal of Lys63-linked ubiquitination in TRAF5 and TRAF6 mediated by the adaptor Act1. Thus, our results demonstrate that USP25 is a deubiquitinating enzyme (DUB) that negatively regulates IL-17-triggered signaling.
authors.affiliation: Department of Immunology and Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhong
authors.forename: Xikui
authors.initials: X
authors.lastname: Liu
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Wang
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Chang
authors.forename: Xindong
authors.initials: X
authors.lastname: Liu
authors.forename: Aibo
authors.initials: A
authors.lastname: Wang
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Reynolds
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology; D000818:Animals; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology; D017353:Gene Deletion; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D020381:Interleukin-17 / Q000235:genetics* / Q000276:immunology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology; D048015:TNF Receptor-Associated Factor 5 / Q000235:genetics / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology; D043222:Ubiquitin Thiolesterase / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D020381:Interleukin-17; D048015:TNF Receptor-Associated Factor 5; D048029:TNF Receptor-Associated Factor 6; C515963:Traf3ip2 protein, mouse; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D048670:MAP Kinase Kinase 4; D043222:Ubiquitin Thiolesterase