title: Regulation of intestinal homeostasis by the ulcerative colitis-associated gene RNF186.
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.
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.|Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Fujimoto
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.|Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kinoshita
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: DNA-Chip Development Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Okuzaki
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.|Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Shimada
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.|Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Kayama
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.|Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Ryu
authors.initials: R
authors.lastname: Okumura
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.|Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Yoki
authors.initials: Y
authors.lastname: Furuta
authors.affiliation: Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Narazaki
authors.affiliation: Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tamura
authors.affiliation: Department of Biochemistry, Graduate School of Medicine, Hokkaido University, Hokkaido, Japan.
authors.forename: Shigetsugu
authors.initials: S
authors.lastname: Hatakeyama
authors.affiliation: Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Ikawa
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan.|Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.affiliation: Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan.|Laboratory of Biological Science, Graduate School of Frontier Biosciences and Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tsukita
authors.affiliation: Laboratory of Immune Regulation, Department of Microbiology and Immunology, Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.|Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takeda
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000235:genetics*; D003106:Colon / Q000473:pathology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D010539:Permeability; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D000070584:Tripartite Motif Proteins; D016264:Dextran Sulfate; C000624425:Rnf186 protein, mouse; C115437:TRIM17 protein, human; D044767:Ubiquitin-Protein Ligases