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 Ire1α or germline Ire1β deletion, and subsequently with double deleted Ire1α, Ire1β mice. At baseline, intestine-specific Ire1α deleted mice and mice with germline Ire1β deletion exhibited no morphologic changes in small intestine or colon, but double deleted Ire1α ^-/- Ire1β ^-/- mice developed progressive intestinal and colonic injury and tumorigenesis. In contrast to single-deleted IECs, RNA-Seq from Ire1α ^-/- Ire1β ^-/- 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^min), we observed that loss of either intestinal epithelial Ire1α or of Ire1β alone produced a growth advantage, increasing tumor burden. IRE1α mediated splicing of Xbp1 mRNA was maintained following Ire1β deletion but not in double deleted Ire1α ^-/- Ire1β ^-/- mice. Increased expression of either Ire1α or Ire1β 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.