title: The REGγ-proteasome forms a regulatory circuit with IκBɛ and NFκB in experimental colitis.
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.
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Jinjin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ji
authors.affiliation: The Fifth Hospital of Shanghai, Fudan University, Shanghai 200240, China.
authors.forename: Fengyuan
authors.initials: F
authors.lastname: Chen
authors.affiliation: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.|Department of Microbiology, Immunology, and Molecular Genetics and Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, California 90025, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Fortmann
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Qingwu
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Weicang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Qingwei
authors.initials: Q
authors.lastname: Wang
authors.affiliation: The Institute of Aging Research, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Zheng
authors.affiliation: Department of Pathology, the Second Chengdu Municipal Hospital, Chengdu 610017, China.
authors.forename: Pei
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Biology, The Dan L. Duncan Cancer Center, Baylor College of Medicine. One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Shixia
authors.initials: S
authors.lastname: Huang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Tieliu
authors.initials: T
authors.lastname: Shi
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Biaohong
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Yongyan
authors.initials: Y
authors.lastname: Dang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Jiwu
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Biology, The Dan L. Duncan Cancer Center, Baylor College of Medicine. One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.affiliation: Department of Molecular and Cellular Biology, The Dan L. Duncan Cancer Center, Baylor College of Medicine. One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Robb E
authors.initials: RE
authors.lastname: Moses
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China.
authors.forename: Jianru
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Signaling Systems Laboratory and San Diego Center for Systems Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.|Department of Molecular and Cellular Biology, The Dan L. Duncan Cancer Center, Baylor College of Medicine. One Baylor Plaza, Houston, Texas 77030, USA.
authors.forename: Xiaotao
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000150:complications / Q000201:enzymology*; D003110:Colonic Neoplasms / Q000209:etiology; D016264:Dextran Sulfate; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*
chemical_list: D001324:Autoantigens; C099558:Ki antigen; D016328:NF-kappa B; D016264:Dextran Sulfate; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex