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

Nature Immunology volume 13, pages 1110–1117 (2012)Cite this article

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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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Figure 1: Overexpression of USP25 inhibits IL-17-triggered signaling.
Figure 2: USP25 deficiency enhances the IL-17-induced expression of proinflammatory cytokines.
Figure 3: IL-17-induced pulmonary inflammation is enhanced in the absence of USP25.
Figure 4: USP25 deficiency exacerbates the severity of EAE.
Figure 5: USP25 and its DUB activity are required for restriction of IL-17 signaling.
Figure 6: USP25 negatively regulates the IL-17-mediated stabilization of chemokine-encoding mRNA.
Figure 7: IL-17 induces the USP25-TRAF5 and USP25-TRAF6 associations.
Figure 8: USP25 deubiquitinates Act1-mediated K63-linked ubiquitination of TRAF6 and TRAF5.

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Acknowledgements

We thank G. Marfany (University of Barcelona) for rabbit anti-USP25; T. Hamilton (Cleveland Clinic) for Tet-Off HeLa cells and pTRE2-KCΔ4 plasmid; Z. Chen (UT Southwestern Medical Center) for hemagglutinin-tagged ubiquitin (K48 only and K63 only) and suggestions; H.-B. Shu (Wuhan University) for mouse anti-TRAF6, plasmids encoding TRAF1–TRAF6 and suggestions; and members of Dong laboratory for technical help. Supported by the US National Institutes of Health, the University of Texas MD Anderson Cancer Center, the CFP foundation of MD Anderson Cancer Center (B.Z.) and the Leukemia and Lymphoma Society (C.D.).

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Authors and Affiliations

  1. Department of Immunology and Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Bo Zhong, Xikui Liu, Xiaohu Wang, Seon Hee Chang, Xindong Liu, Aibo Wang, Joseph M Reynolds & Chen Dong

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Contributions

B.Z., Xik.L. and C.D. designed the project; Xik.L. did the IL-17-induced peritoneal inflammation experiments; B.Z., X.W., Xin.L. and A.W. did the biochemical experiments and EAE analysis; B.Z. and S.H.C. prepared MEFs and did the IL-17 induced lung-inflammation experiments; B.Z. and J.M.R. prepared lung epithelial cells; and B.Z. and C.D. wrote and revised the manuscript.

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Correspondence to Chen Dong.

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Zhong, B., Liu, X., Wang, X. et al. Negative regulation of IL-17-mediated signaling and inflammation by the ubiquitin-specific protease USP25. Nat Immunol 13, 1110–1117 (2012). https://doi.org/10.1038/ni.2427

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