The REGγ 3-proteasome forms a regulatory circuit with Iκ BIκ and NFκB in experimental colitis

Jinjin Xu, Lei Zhou, Lei Ji, Fengyuan Chen, Karen Fortmann, Kun Zhang, Qingwu Liu, Ke Li, Weicang Wang, Hao Wang, Wei Xie, Qingwei Wang, Jiang Liu, Biao Zheng, Pei Zhang, Shixia Huang, Tieliu Shi, Biaohong Zhang, Yongyan Dang, Jiwu ChenBert W. Omalley, Robb E. Moses, Ping Wang, Lei Li, Jianru Xiao, Alexander Hoffmann, Xiaotao Li

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Increasing incidence of inflammatory bowel disorders demands a better understanding of the molecular mechanisms underlying its multifactorial aetiology. Here we demonstrate that mice deficient for REGI 3, a proteasome activator, show significantly attenuated intestinal inflammation and colitis-Associated cancer in dextran sodium sulfate model. Bone marrow transplantation experiments suggest that REGI 3â € s function in non-haematopoietic cells primarily contributes to the phenotype. Elevated expression of REGI 3 exacerbates local inflammation and promotes a reciprocal regulatory loop with NFI° B involving ubiquitin-independent degradation of II° BI>. Additional deletion of II° BI> restored colitis phenotypes and inflammatory gene expression in REGI 3-deficient mice. In sum, this study identifies REGI 3-mediated control of II° BI> as a molecular mechanism that contributes to NFI° B activation and promotes bowel inflammation and associated tumour formation in response to chronic injury.

Original languageEnglish (US)
Article number10761
JournalNature communications
Volume7
DOIs
StatePublished - Feb 22 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Xu, J., Zhou, L., Ji, L., Chen, F., Fortmann, K., Zhang, K., Liu, Q., Li, K., Wang, W., Wang, H., Xie, W., Wang, Q., Liu, J., Zheng, B., Zhang, P., Huang, S., Shi, T., Zhang, B., Dang, Y., ... Li, X. (2016). The REGγ 3-proteasome forms a regulatory circuit with Iκ BIκ and NFκB in experimental colitis. Nature communications, 7, [10761]. https://doi.org/10.1038/ncomms10761