The REGγ-proteasome forms a regulatory circuit with IκBɛ 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 Chen, Bert W. O’Malley, Robb E. Moses, Ping Wang, Lei Li, Jianru Xiao (), Alexander Hoffmann () and Xiaotao Li ()
Additional contact information
Jinjin Xu: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Lei Zhou: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Lei Ji: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Fengyuan Chen: The Fifth Hospital of Shanghai, Fudan University
Karen Fortmann: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California
Kun Zhang: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Qingwu Liu: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Ke Li: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Weicang Wang: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Hao Wang: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Wei Xie: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Qingwei Wang: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Jiang Liu: The Institute of Aging Research, School of Medicine, Hangzhou Normal University
Biao Zheng: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Pei Zhang: the Second Chengdu Municipal Hospital
Shixia Huang: The Dan L. Duncan Cancer Center, Baylor College of Medicine. One Baylor Plaza
Tieliu Shi: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Biaohong Zhang: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Yongyan Dang: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Jiwu Chen: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Bert W. O’Malley: The Dan L. Duncan Cancer Center, Baylor College of Medicine. One Baylor Plaza
Robb E. Moses: The Dan L. Duncan Cancer Center, Baylor College of Medicine. One Baylor Plaza
Ping Wang: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Lei Li: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University
Jianru Xiao: Changzheng Hospital, The Second Military Medical University
Alexander Hoffmann: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California
Xiaotao Li: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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 REGγ, a proteasome activator, show significantly attenuated intestinal inflammation and colitis-associated cancer in dextran sodium sulfate model. Bone marrow transplantation experiments suggest that REGγ’s function in non-haematopoietic cells primarily contributes to the phenotype. Elevated expression of REGγ exacerbates local inflammation and promotes a reciprocal regulatory loop with NFκB involving ubiquitin-independent degradation of IκBɛ. Additional deletion of IκBɛ restored colitis phenotypes and inflammatory gene expression in REGγ-deficient mice. In sum, this study identifies REGγ-mediated control of IκBɛ as a molecular mechanism that contributes to NFκB activation and promotes bowel inflammation and associated tumour formation in response to chronic injury.

Date: 2016
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DOI: 10.1038/ncomms10761

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