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

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.