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 Chen; Bert W. Omalley; Robb E. Moses; Ping Wang; Lei Li; Jianru Xiao; Alexander Hoffmann; Xiaotao Li

doi:10.1038/ncomms10761

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

Molecular & Medical Genetics

Research output: Contribution to journal › Article › peer-review

48 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 language	English (US)
Article number	10761
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10761
State	Published - Feb 22 2016

ASJC Scopus subject areas

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

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10.1038/ncomms10761

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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

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, Chen, J, Omalley, BW, Moses, RE, Wang, P, Li, L, Xiao, J, Hoffmann, A & Li, X 2016, 'The REGγ 3-proteasome forms a regulatory circuit with Iκ BIκ and NFκB in experimental colitis', Nature communications, vol. 7, 10761. https://doi.org/10.1038/ncomms10761

@article{dfa2d3a191ee44b098b7550dafa9ce14,

title = "The REGγ 3-proteasome forms a regulatory circuit with Iκ BIκ 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 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 3{\^a} € 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.",

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

note = "Funding Information: This work was supported by the National Basic Research Program of China (2011CB504200 and 2015CB910403), the National Natural Science Foundation of China (81471066, 81261120555, 31071875 and 31200878) and the Science and Technology Commission of Shanghai Municipality (14430712100), and the US National Institutes of Health (P01GM071862 and R01GM071573). We thank Dr Francesco J. DeMayo and the animal core at the department of Molecular and Cellular Biology for assistance in animal works.",

year = "2016",

month = feb,

day = "22",

doi = "10.1038/ncomms10761",

language = "English (US)",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

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T1 - The REGγ 3-proteasome forms a regulatory circuit with Iκ BIκ and NFκB in experimental colitis

AU - Xu, Jinjin

AU - Zhou, Lei

AU - Ji, Lei

AU - Chen, Fengyuan

AU - Fortmann, Karen

AU - Zhang, Kun

AU - Liu, Qingwu

AU - Li, Ke

AU - Wang, Weicang

AU - Wang, Hao

AU - Xie, Wei

AU - Wang, Qingwei

AU - Liu, Jiang

AU - Zheng, Biao

AU - Zhang, Pei

AU - Huang, Shixia

AU - Shi, Tieliu

AU - Zhang, Biaohong

AU - Dang, Yongyan

AU - Chen, Jiwu

AU - Omalley, Bert W.

AU - Moses, Robb E.

AU - Wang, Ping

AU - Li, Lei

AU - Xiao, Jianru

AU - Hoffmann, Alexander

AU - Li, Xiaotao

N1 - Funding Information: This work was supported by the National Basic Research Program of China (2011CB504200 and 2015CB910403), the National Natural Science Foundation of China (81471066, 81261120555, 31071875 and 31200878) and the Science and Technology Commission of Shanghai Municipality (14430712100), and the US National Institutes of Health (P01GM071862 and R01GM071573). We thank Dr Francesco J. DeMayo and the animal core at the department of Molecular and Cellular Biology for assistance in animal works.

PY - 2016/2/22

Y1 - 2016/2/22

N2 - 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.

AB - 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.

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

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