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

Intestinal epithelial cells (IECs) uniquely express two IRE1 paralogues, IRE1α and IRE1β, whose roles in intestinal physiology are incompletely understood. We examined the individual and cooperative functions of IRE1α and IRE1β in IECs using mice using intestine-specific deletion of or germline deletion, and subsequently with double mice. At baseline, intestine-specific deleted mice and mice with germline deletion exhibited no morphologic changes in small intestine or colon, but double deleted mice developed progressive intestinal and colonic injury and tumorigenesis. In contrast to single-deleted IECs, RNA-Seq from 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 (APC), we observed that loss of either intestinal epithelial or of alone produced a growth advantage, increasing tumor burden. IRE1α mediated splicing of mRNA was maintained following deletion but not in double deleted mice. Increased expression of either or 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.