Negative regulation of IL-17-mediated signaling and inflammation by the ubiquitin-specific protease USP25

Nat Immunol. 2012 Nov;13(11):1110-7. doi: 10.1038/ni.2427. Epub 2012 Oct 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / immunology
  • Animals
  • Chemokine CXCL1 / genetics
  • Chemokine CXCL1 / immunology
  • Gene Deletion
  • Gene Expression
  • Gene Expression Regulation / immunology
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / immunology
  • Inflammation / genetics*
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-17 / genetics*
  • Interleukin-17 / immunology
  • MAP Kinase Kinase 4 / genetics
  • MAP Kinase Kinase 4 / immunology
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Signal Transduction / genetics*
  • Signal Transduction / immunology
  • TNF Receptor-Associated Factor 5 / genetics
  • TNF Receptor-Associated Factor 5 / immunology
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / immunology
  • Ubiquitin Thiolesterase / deficiency
  • Ubiquitin Thiolesterase / genetics*
  • Ubiquitin Thiolesterase / immunology
  • Ubiquitination

Substances

  • 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