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Mucosal Immunol. 2017 Mar;10(2):446-459. doi: 10.1038/mi.2016.58. Epub 2016 Jul 6.

Regulation of intestinal homeostasis by the ulcerative colitis-associated gene RNF186.

Author information

1
Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
2
Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan.
3
Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
4
Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
5
DNA-Chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
6
Department of Biochemistry, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.
7
Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
8
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.

Abstract

Genome-wide association studies and subsequent deep sequencing analysis have identified susceptible loci for inflammatory bowel diseases (IBDs) including ulcerative colitis (UC). A gene encoding RING finger protein 186 (RNF186) is located within UC-susceptible loci. However, it is unclear whether RNF186 is involved in IBD pathogenesis. Here, we show that RNF186 controls protein homeostasis in colonic epithelia and regulates intestinal inflammation. RNF186, which was highly expressed in colonic epithelia, acted as an E3 ligase mediating polyubiquitination of its substrates. Permeability of small organic molecules was augmented in the intestine of Rnf186-/- mice. Increased expression of several RNF186 substrates, such as occludin, was found in Rnf186-/- colonic epithelia. The disturbed protein homeostasis in Rnf186-/- mice correlated with enhanced endoplasmic reticulum (ER) stress in colonic epithelia and increased sensitivity to intestinal inflammation after dextran sulfate sodium (DSS) treatment. Introduction of an UC-associated Rnf186 mutation led to impaired E3 ligase activity and increased sensitivity to DSS-induced intestinal inflammation in mice. Thus, RNF186 maintains gut homeostasis by controlling ER stress in colonic epithelia.

PMID:
27381925
DOI:
10.1038/mi.2016.58
[Indexed for MEDLINE]

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