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May 7th, 2025
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SBP Medical Discovery Institute
cancer biology
biorxiv

IRE1α and IRE1β Protect Intestinal Epithelium and Suppress Colorectal Tumorigenesis through Distinct Mechanisms

Deng, R.Open in Google Scholar•Wang, M.Open in Google Scholar•Promlek, T.Open in Google Scholar•Druelle-Cedano, C.Open in Google Scholar•Murad, R.Open in Google Scholar•Davidson, N. O.Open in Google Scholar•Kaufman, R. J.Open in Google Scholar

Intestinal epithelial cells (IECs) uniquely express two IRE1 paralogues, IRE1 and IRE1{beta}, whose roles in intestinal physiology are incompletely understood. We examined the individual and cooperative functions of IRE1 and IRE1{beta} in IECs using mice using intestine-specific deletion of Ire1 or germline Ire1{beta} deletion, and subsequently with double deleted Ire1, Ire1{beta} mice. At baseline, intestine-specific Ire1 deleted mice and mice with germline Ire1{beta} deletion exhibited no morphologic changes in small intestine or colon, but double deleted Ire1-/-Ire1{beta}-/- mice developed progressive intestinal and colonic injury and tumorigenesis. In contrast to single-deleted IECs, RNA-Seq from Ire1-/-Ire1{beta}-/- IECs revealed decreased expression of defense-associated mRNAs, together with increased expression of inflammatory and pathogenic mRNAs. Utilizing orthogonal models of intestinal tumorigenesis, reflecting either inflammatory-mutagenic injury (AOM-DSS) or spontaneous polyposis (APCmin), we observed that loss of either intestinal epithelial Ire1 or of Ire1{beta} alone produced a growth advantage, increasing tumor burden. IRE1 mediated splicing of Xbp1 mRNA was maintained following Ire1{beta} deletion but not in double deleted Ire1-/-Ire1{beta}-/- mice. Increased expression of either Ire1 or Ire1{beta} mRNA was associated with improved survival in patients with colorectal cancer. Taken together our findings suggest IRE1 paralogues utilize essential but distinct mechanisms to safeguard intestinal homeostasis and suppress tumorigenesis.

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