1. The epithelial-specific ER stress sensor ERN2/IRE1[beta] enables host-microbiota crosstalk to affect colon goblet cell development
- Author
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Grey, Michael J., de Luca, Heidi, Ward, Doyle V., Kreulen, Irini A.M., Gwilt, Katlynn Bugda, Foley, Sage E., Thiagarajah, Jay R., McCormick, Beth A., Turner, Jerrold R., and Lencer, Wayne I.
- Subjects
Microbiota (Symbiotic organisms) -- Physiological aspects -- Health aspects ,Endoplasmic reticulum -- Physiological aspects -- Health aspects ,Colon (Anatomy) -- Physiological aspects -- Health aspects ,Host-bacteria relationships -- Physiological aspects -- Health aspects ,Membrane proteins -- Physiological aspects -- Health aspects ,Epithelial cells -- Physiological aspects -- Health aspects ,Health care industry - Abstract
Epithelial cells lining mucosal surfaces of the gastrointestinal and respiratory tracts uniquely express ERN2/IRE1[beta], a paralogue of the most evolutionarily conserved endoplasmic reticulum stress sensor, ERN1/IRE1[alpha]. How ERN2 functions at the host-environment interface and why a second paralogue evolved remain incompletely understood. Using conventionally raised and germ-free [Ern2.sup.-/-] mice, we found that ERN2 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 Ern2 expression. ERN2 acted by splicing Xbp1 mRNA to expand ER function and prevent ER stress in goblet cells. Although ERN1 can also splice Xbp1 mRNA, it did not act redundantly to ERN2 in this context. By regulating assembly of the colon mucus layer, ERN2 further shaped the composition of the gut microbiota. Mice lacking Ern2 had a dysbiotic microbial community that failed to induce goblet cell development and increased susceptibility to colitis when transferred into germ-free WT mice. These results show that ERN2 evolved at mucosal surfaces to mediate crosstalk between gut microbes and the colonic epithelium required for normal homeostasis and host defense., Introduction Epithelial cells lining mucosal surfaces of the gastrointestinal (GI) and respiratory tracts express 2 paralogues of the most evolutionarily conserved endoplasmic reticulum (ER) stress sensor IRE1. While all cell [...]
- Published
- 2022
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