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.
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Authors | Bo Zhong, Xikui Liu, Xiaohu Wang, Seon Hee Chang, Xindong Liu, Aibo Wang, Joseph M Reynolds, Chen Dong |
Journal | Nature immunology
(Nat Immunol)
Vol. 13
Issue 11
Pg. 1110-7
(Nov 2012)
ISSN: 1529-2916 [Electronic] United States |
PMID | 23042150
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Adaptor Proteins, Signal Transducing
- Chemokine CXCL1
- Cxcl1 protein, mouse
- Interleukin-17
- TNF Receptor-Associated Factor 5
- TNF Receptor-Associated Factor 6
- Traf3ip2 protein, mouse
- Chuk protein, mouse
- I-kappa B Kinase
- MAP Kinase Kinase 4
- Ubiquitin Thiolesterase
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Topics |
- Adaptor Proteins, Signal Transducing
(genetics, immunology)
- Animals
- Chemokine CXCL1
(genetics, immunology)
- Gene Deletion
- Gene Expression
- Gene Expression Regulation
(immunology)
- I-kappa B Kinase
(genetics, immunology)
- Inflammation
(genetics, immunology, pathology)
- Interleukin-17
(genetics, immunology)
- MAP Kinase Kinase 4
(genetics, immunology)
- Mice
- Mice, Knockout
- Phosphorylation
- Signal Transduction
(genetics, immunology)
- TNF Receptor-Associated Factor 5
(genetics, immunology)
- TNF Receptor-Associated Factor 6
(genetics, immunology)
- Ubiquitin Thiolesterase
(deficiency, genetics, immunology)
- Ubiquitination
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