Increased sensitivity to dextran sodium sulfate colitis in IRE1beta-deficient mice.
The epithelial cells of the gastrointestinal tract are exposed to toxins and infectious agents that can adversely affect protein folding in the endoplasmic reticulum (ER) and cause ER stress. The IRE1 genes are implicated in sensing and responding to ER stress signals. We found that epithelial cells of the gastrointestinal tract express IRE1beta, a specific isoform of IRE1. BiP protein, a marker of ER stress, was elevated in the colonic mucosa of IRE1beta(-/-) mice, and, when exposed to dextran sodium sulfate (DSS) to induce inflammatory bowel disease, mutant mice developed colitis 3-5 days earlier than did wild-type or IRE1beta(+/-) mice. The inflammation marker ICAM-1 was also expressed earlier in the colonic mucosa of DSS-treated IRE1beta(-/-) mice, indicating that the mutation had its impact early in the inflammatory process, before the onset of mucosal ulceration. These findings are consistent with a model whereby perturbations in ER function, which are normally mitigated by the activity of IRE1beta, participate in the development of colitis.
Skirball Institute of Biomolecular Medicine, Departments of Medicine and Cell Biology, and the Kaplan Cancer Center, New York University School of Medicine, New York, New York, USA.
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A
Bertolotti
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Wang
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Novoa
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Jungreis
K
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Schlessinger
J H
JH
Cho
A B
AB
West
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D
Ron
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis; D003092:Colitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D015212:Inflammatory Bowel Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000096:biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D020033:Protein Isoforms; D018799:Intercellular Adhesion Molecule-1; D016264:Dextran Sulfate; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases