{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T04:42:38Z","timestamp":1775968958982,"version":"3.50.1"},"posted":{"date-parts":[[2025,5,7]]},"group-title":"Cancer Biology","reference-count":43,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T00:00:00Z","timestamp":1746576000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NIH\/NCI","award":["DK113171"],"award-info":[{"award-number":["DK113171"]}]},{"name":"NIH\/NCI","award":["DK103185"],"award-info":[{"award-number":["DK103185"]}]},{"name":"NIH\/NCI","award":["DK110973"],"award-info":[{"award-number":["DK110973"]}]},{"name":"NIH\/NCI","award":["CA198103"],"award-info":[{"award-number":["CA198103"]}]},{"name":"NIH\/NCI","award":["HL160472"],"award-info":[{"award-number":["HL160472"]}]},{"name":"NIH\/NCI","award":["CA281819"],"award-info":[{"award-number":["CA281819"]}]},{"DOI":"10.13039\/100011684","name":"Crohn's and Colitis Foundation","doi-asserted-by":"crossref","award":["Litwin Pioneers in IBD 717640"],"award-info":[{"award-number":["Litwin Pioneers in IBD 717640"]}],"id":[{"id":"10.13039\/100011684","id-type":"DOI","asserted-by":"crossref"}]},{"name":"SBP NCI Cancer Center Grant","award":["P30 CA030199"],"award-info":[{"award-number":["P30 CA030199"]}]},{"name":"San Diego Digestive Diseases Research Center Grant","award":["P30 DK120515"],"award-info":[{"award-number":["P30 DK120515"]}]},{"name":"NIH","award":["DK119437"],"award-info":[{"award-number":["DK119437"]}]},{"name":"NIH","award":["DK128169"],"award-info":[{"award-number":["DK128169"]}]},{"name":"NIH","award":["P30DK52574"],"award-info":[{"award-number":["P30DK52574"]}]},{"name":"NIH","award":["HL151328"],"award-info":[{"award-number":["HL151328"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Intestinal epithelial cells (IECs) uniquely express two IRE1 paralogues, IRE1\u03b1 and IRE1\u03b2, whose roles in intestinal physiology are incompletely understood. We examined the individual and cooperative functions of IRE1\u03b1 and IRE1\u03b2 in IECs using mice using intestine-specific deletion of\n                  <jats:italic>Ire1\u03b1<\/jats:italic>\n                  or germline\n                  <jats:italic>Ire1\u03b2<\/jats:italic>\n                  deletion, and subsequently with double\n                  <jats:italic>deleted Ire1\u03b1, Ire1\u03b2<\/jats:italic>\n                  mice. At baseline, intestine-specific\n                  <jats:italic>Ire1\u03b1<\/jats:italic>\n                  deleted mice and mice with germline\n                  <jats:italic>Ire1\u03b2<\/jats:italic>\n                  deletion exhibited no morphologic changes in small intestine or colon, but double deleted\n                  <jats:italic>\n                    Ire1\u03b1\n                    <jats:sup>-\/-<\/jats:sup>\n                    Ire1\u03b2\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  mice developed progressive intestinal and colonic injury and tumorigenesis. In contrast to single-deleted IECs, RNA-Seq from\n                  <jats:italic>\n                    Ire1\u03b1\n                    <jats:sup>-\/-<\/jats:sup>\n                    Ire1\u03b2\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  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\n                  <jats:sup>min<\/jats:sup>\n                  ), we observed that loss of either intestinal epithelial\n                  <jats:italic>Ire1\u03b1<\/jats:italic>\n                  or of\n                  <jats:italic>Ire1\u03b2<\/jats:italic>\n                  alone produced a growth advantage, increasing tumor burden. IRE1\u03b1 mediated splicing of\n                  <jats:italic>Xbp1<\/jats:italic>\n                  mRNA was maintained following\n                  <jats:italic>Ire1\u03b2<\/jats:italic>\n                  deletion but not in double deleted\n                  <jats:italic>\n                    Ire1\u03b1\n                    <jats:sup>-\/-<\/jats:sup>\n                    Ire1\u03b2\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  mice. Increased expression of either\n                  <jats:italic>Ire1\u03b1<\/jats:italic>\n                  or\n                  <jats:italic>Ire1\u03b2<\/jats:italic>\n                  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.\n                <\/jats:p>","DOI":"10.1101\/2025.05.01.651751","type":"posted-content","created":{"date-parts":[[2025,5,7]],"date-time":"2025-05-07T17:40:10Z","timestamp":1746639610000},"source":"Crossref","is-referenced-by-count":1,"title":["IRE1\u03b1 and IRE1\u03b2 Protect Intestinal Epithelium and Suppress Colorectal Tumorigenesis through Distinct Mechanisms"],"prefix":"10.64898","author":[{"given":"Ruishu","family":"Deng","sequence":"first","affiliation":[{"name":"Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, SBP Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miao","family":"Wang","sequence":"additional","affiliation":[{"name":"Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, SBP Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thanyarat","family":"Promlek","sequence":"additional","affiliation":[{"name":"Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, SBP Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clementine","family":"Druelle-Cedano","sequence":"additional","affiliation":[{"name":"Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, SBP Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rabi","family":"Murad","sequence":"additional","affiliation":[{"name":"Bioinformatics Core, SBP Medical Discovery Institute, 10901 N. Torrey Pines Rd., La Jolla CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas O.","family":"Davidson","sequence":"additional","affiliation":[{"name":"Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4277-316X","authenticated-orcid":false,"given":"Randal J.","family":"Kaufman","sequence":"additional","affiliation":[{"name":"Degenerative Diseases Program, Center for Genetic Disorders and Aging Research, SBP Medical Discovery Institute, 10901 N. 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