The epithelial-specific ER stress sensor IRE1β enables host-microbiota crosstalk to affect colon goblet cell development
The epithelial-specific ER stress sensor IRE1β enables host-microbiota crosstalk to affect colon goblet cell development
ABSTRACT Epithelial cells lining mucosal surfaces of the gastrointestinal and respiratory tracts uniquely express IRE1β (Ern2), a paralogue of the most evolutionarily conserved endoplasmic reticulum stress sensor IRE1α. How IRE1β functions at the host-environment interface and why a second IRE1 paralogue evolved remain incompletely understood. Using conventionally raised and germ-free Ern2-/- mice, we found that IRE1β was required for microbiota-induced goblet cell maturation and mucus barrier assembly in the colon. This occurred only after colonization of the alimentary tract with normal gut microflora, which induced IRE1β expression. IRE1β acted by splicing Xbp1 mRNA to expand ER function and prevent ER stress in goblet cells. Although IRE1α can also splice Xbp1 mRNA, it did not act redundantly to IRE1β in this context. By regulating assembly of the colon mucus layer, IRE1β further shaped the composition of the gut microbiota. Mice lacking IRE1β had a dysbiotic microbial community that failed to induce goblet cell development when transferred into germ-free wild type mice. These results show that IRE1β evolved at mucosal surfaces to mediate crosstalk between gut microbes and the colonic epithelium required for normal homeostasis and host defense.
Grey Michael J.、Luca Heidi De、McCormick Beth A.、Turner Jerrold R.、Foley Sage E.、Thiagarajah Jay R.、Lencer Wayne I.、Kreulen Irini A. M.、Ward Doyle V.
Division of Gastroenterology and Nutrition, Boston Children?ˉs Hospital||Department of Pediatrics, Harvard Medical School||Harvard Digestive Disease Center, Boston Children?ˉs HospitalDivision of Gastroenterology and Nutrition, Boston Children?ˉs HospitalDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School||Program in Microbiome Dynamics, University of Massachusetts Medical SchoolHarvard Digestive Disease Center, Boston Children?ˉs Hospital||Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women?ˉs Hospital||Departments of Pathology and Medicine, Harvard Medical SchoolDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School||Program in Microbiome Dynamics, University of Massachusetts Medical SchoolDivision of Gastroenterology and Nutrition, Boston Children?ˉs Hospital||Department of Pediatrics, Harvard Medical School||Harvard Digestive Disease Center, Boston Children?ˉs HospitalDivision of Gastroenterology and Nutrition, Boston Children?ˉs Hospital||Department of Pediatrics, Harvard Medical School||Harvard Digestive Disease Center, Boston Children?ˉs HospitalDivision of Gastroenterology and Nutrition, Boston Children?ˉs Hospital||Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of AmsterdamDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School||Program in Microbiome Dynamics, University of Massachusetts Medical School
细胞生物学分子生物学微生物学
Grey Michael J.,Luca Heidi De,McCormick Beth A.,Turner Jerrold R.,Foley Sage E.,Thiagarajah Jay R.,Lencer Wayne I.,Kreulen Irini A. M.,Ward Doyle V..The epithelial-specific ER stress sensor IRE1β enables host-microbiota crosstalk to affect colon goblet cell development[EB/OL].(2025-03-28)[2025-04-27].https://www.biorxiv.org/content/10.1101/2021.07.28.453864.点此复制
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