The epithelial-specific ER stress sensor IRE1β enables host-microbiota crosstalk to affect colon goblet cell development

Grey, M. J.; De Luca, H.; Ward, D. V.; Kreulen, I. A. M.; Foley, S. E.; Thiagarajah, J. R.; McCormick, B. A.; Turner, J. R.; Lencer, W. I.

doi:10.1101/2021.07.28.453864

bioRxiv · 10.1101/2021.07.28.453864

The epithelial-specific ER stress sensor IRE1β enables host-microbiota crosstalk to affect colon goblet cell development

Grey, M. J.·De Luca, H.·Ward, D. V.·Kreulen, I. A. M.·Foley, S. E.·Thiagarajah, J. R.·McCormick, B. A.·Turner, J. R.·Lencer, W. I.

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Abstract

Epithelial cells lining mucosal surfaces of the gastrointestinal and respiratory tracts uniquely express IRE1{beta} (Ern2), a paralogue of the most evolutionarily conserved endoplasmic reticulum stress sensor IRE1. How IRE1{beta} 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 IRE1{beta} 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 IRE1{beta} expression. IRE1{beta} acted by splicing Xbp1 mRNA to expand ER function and prevent ER stress in goblet cells. Although IRE1 can also splice Xbp1 mRNA, it did not act redundantly to IRE1{beta} in this context. By regulating assembly of the colon mucus layer, IRE1{beta} further shaped the composition of the gut microbiota. Mice lacking IRE1{beta} had a dysbiotic microbial community that failed to induce goblet cell development when transferred into germ-free wild type mice. These results show that IRE1{beta} evolved at mucosal surfaces to mediate crosstalk between gut microbes and the colonic epithelium required for normal homeostasis and host defense.

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Grey, M. J., De Luca, H., Ward, D. V., Kreulen, I. A. M., Foley, S. E., Thiagarajah, J. R., McCormick, B. A., Turner, J. R., Lencer, W. I.. 2021-07-28. The epithelial-specific ER stress sensor IRE1β enables host-microbiota crosstalk to affect colon goblet cell development. https://doi.org/10.1101/2021.07.28.453864

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