{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T20:02:48Z","timestamp":1792267368318,"version":"4.4.0"},"posted":{"date-parts":[[2026,1,3]]},"group-title":"Pathology","reference-count":66,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T00:00:00Z","timestamp":1767398400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010390","name":"Saint Louis University","doi-asserted-by":"crossref","award":["Startup fund"],"award-info":[{"award-number":["Startup fund"]}],"id":[{"id":"10.13039\/100010390","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010390","name":"Saint Louis University","doi-asserted-by":"crossref","award":["seed grant from the SLU Department of Pharmacology and Physiology"],"award-info":[{"award-number":["seed grant from the SLU Department of Pharmacology and Physiology"]}],"id":[{"id":"10.13039\/100010390","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010390","name":"Saint Louis University","doi-asserted-by":"crossref","award":["President Research Fund"],"award-info":[{"award-number":["President Research Fund"]}],"id":[{"id":"10.13039\/100010390","id-type":"DOI","asserted-by":"crossref"}]},{"award":["R01DK132162"],"award-info":[{"award-number":["R01DK132162"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Ubiquitin-dependent signaling is essential for maintaining intestinal homeostasis and its dysregulation contributes to chronic intestinal disorders, such as Inflammatory Bowel Disease (IBD). Ube4A is a U-box E3\/E4 ubiquitin ligase involved in lipid metabolism and insulin signaling in metabolic tissues. Autoantibodies against Ube4A have been identified in patients with IBD and are associated with disease long-term complications. Despite these clinical associations, the physiological role of Ube4A in the gastrointestinal tract remains unknown. This study aimed to define the function of Ube4A in the colon and determine how its loss influences susceptibility to experimental colitis.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    <jats:italic>UBE4A<\/jats:italic>\n                    expression in human colonic tissue from healthy individuals and patients with IBD was analyzed using publicly available single-cell RNA sequencing datasets. The role of Ube4A in colonic homeostasis and colitis pathogenesis was examined using global Ube4A knockout (UKO) mice subjected to dextran sulfate sodium (DSS)-induced colitis. UKO colon phenotypes were characterized using transcriptomic analyses, immunofluorescence, and flow cytometry.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    <jats:italic>UBE4A<\/jats:italic>\n                    is highly expressed in human colonic epithelial cells, and its expression is reduced from healthy to IBD inflamed tissues. In mice, Ube4A deficiency significantly exacerbated DSS-induced colitis, as evidenced by increased weight loss, disease activity scores, shortened colon length, and more severe histological injury. Transcriptomic profiling revealed enhanced inflammatory signaling, alongside dysregulation of lipid transport and storage, as well as antimicrobial defense pathways. DSS-treated UKO mice also exhibited increased mast cell activation and elevated expression of matrix metalloproteinases. Importantly, colons from UKO mice displayed baseline transcriptional alterations indicative of epithelial stress and disrupted lipid metabolic programs, even in the absence of injury.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Ube4A is a previously unrecognized regulator of colon homeostasis. Its loss induces existing epithelial stress and metabolic reprogramming that sensitize the colon to exaggerated inflammatory responses during injury such as experimental colitis.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.02.697430","type":"posted-content","created":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T15:25:15Z","timestamp":1767453915000},"source":"Crossref","is-referenced-by-count":1,"title":["Loss of E3 ligase Ube4A Disrupts Colon Homeostasis and Accelerates Experimental Colitis via Altered Lipid Handling"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9560-0046","authenticated-orcid":false,"given":"Simon","family":"Guignard","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7364-7321","authenticated-orcid":false,"given":"Molee","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, USA"},{"name":"Department of Cellular and Systems Pharmacology, University of Florida College of Medicine, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4706-6184","authenticated-orcid":false,"given":"Silvia","family":"Gonzalez-Nieves","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7644-1367","authenticated-orcid":false,"given":"David","family":"DeBruin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Ebert","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasiia","family":"Vinogradskaia","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3460-5599","authenticated-orcid":false,"given":"Michelle","family":"Brennan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8426-2870","authenticated-orcid":false,"given":"Ryan M","family":"Teague","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0100-6530","authenticated-orcid":false,"given":"Anutosh","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, USA"},{"name":"Department of Cellular and Systems Pharmacology, University of Florida College of Medicine, Gainesville, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9940-4106","authenticated-orcid":false,"given":"Vincenza","family":"Cifarelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026010601500436000_2026.01.02.697430v1.1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-060815-014922"},{"key":"2026010601500436000_2026.01.02.697430v1.2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.67.1.425"},{"key":"2026010601500436000_2026.01.02.697430v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2022.01.006"},{"key":"2026010601500436000_2026.01.02.697430v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.imbio.2020.152026"},{"key":"2026010601500436000_2026.01.02.697430v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60751-X"},{"issue":"12","key":"2026010601500436000_2026.01.02.697430v1.6","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.3748\/wjg.v12.i12.1829","article-title":"Current concept on the pathogenesis of inflammatory bowel disease-crosstalk between genetic and microbial factors: pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take \u201ctoll\u201d ?","volume":"12","year":"2006","journal-title":"World J Gastroenterol"},{"key":"2026010601500436000_2026.01.02.697430v1.7","first-page":"7247238","article-title":"A Comprehensive Review and Update on the Pathogenesis of Inflammatory Bowel Disease","volume":"2019","year":"2019","journal-title":"J Immunol Res"},{"key":"2026010601500436000_2026.01.02.697430v1.8","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2021.10.035"},{"issue":"8","key":"2026010601500436000_2026.01.02.697430v1.9","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/S2468-1253(19)30173-6","article-title":"Comorbidities in inflammatory bowel disease: a call for action","volume":"4","year":"2019","journal-title":"Lancet Gastroenterol Hepatol"},{"key":"2026010601500436000_2026.01.02.697430v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/nature11582"},{"key":"2026010601500436000_2026.01.02.697430v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3359"},{"key":"2026010601500436000_2026.01.02.697430v1.12","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2016.09.032"},{"key":"2026010601500436000_2026.01.02.697430v1.13","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2012-303205"},{"key":"2026010601500436000_2026.01.02.697430v1.14","doi-asserted-by":"publisher","DOI":"10.1093\/ecco-jcc\/jjw023"},{"key":"2026010601500436000_2026.01.02.697430v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.01.020"},{"key":"2026010601500436000_2026.01.02.697430v1.16","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20092474"},{"key":"2026010601500436000_2026.01.02.697430v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6103"},{"key":"2026010601500436000_2026.01.02.697430v1.18","doi-asserted-by":"publisher","DOI":"10.1093\/ecco-jcc\/jjaa131"},{"key":"2026010601500436000_2026.01.02.697430v1.19","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e3182088158"},{"key":"2026010601500436000_2026.01.02.697430v1.20","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1705748114"},{"key":"2026010601500436000_2026.01.02.697430v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2017.53"},{"issue":"1","key":"2026010601500436000_2026.01.02.697430v1.22","doi-asserted-by":"crossref","first-page":"17571","DOI":"10.1038\/s41598-022-22295-w","article-title":"Role of the E3 ubiquitin-ligase Hakai in intestinal inflammation and cancer bowel disease","volume":"12","year":"2022","journal-title":"Sci Rep"},{"key":"2026010601500436000_2026.01.02.697430v1.23","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.14.5115"},{"key":"2026010601500436000_2026.01.02.697430v1.24","doi-asserted-by":"publisher","DOI":"10.1002\/ibd.20328"},{"key":"2026010601500436000_2026.01.02.697430v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2018.02.002"},{"key":"2026010601500436000_2026.01.02.697430v1.26","doi-asserted-by":"crossref","first-page":"101767","DOI":"10.1016\/j.molmet.2023.101767","article-title":"Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivo","volume":"75","year":"2023","journal-title":"Mol Metab"},{"key":"2026010601500436000_2026.01.02.697430v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-022-00514-x"},{"key":"2026010601500436000_2026.01.02.697430v1.28","first-page":"15 25 1","article-title":"Dextran sulfate sodium (DSS)-induced colitis in mice","volume":"104","year":"2014","journal-title":"Curr Protoc Immunol"},{"key":"2026010601500436000_2026.01.02.697430v1.29","doi-asserted-by":"publisher","DOI":"10.1126\/science.1260419"},{"key":"2026010601500436000_2026.01.02.697430v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.06.029"},{"key":"2026010601500436000_2026.01.02.697430v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2020.12.020"},{"key":"2026010601500436000_2026.01.02.697430v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.09.015"},{"key":"2026010601500436000_2026.01.02.697430v1.33","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.12.076"},{"issue":"2","key":"2026010601500436000_2026.01.02.697430v1.34","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1093\/ibd\/izaa125","article-title":"Mast Cell Tryptase Promotes Inflammatory Bowel Disease-Induced Intestinal Fibrosis","volume":"27","year":"2021","journal-title":"Inflamm Bowel Dis"},{"key":"2026010601500436000_2026.01.02.697430v1.35","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.2147\/JIR.S288280","article-title":"Metalloproteinases in Inflammatory Bowel Diseases","volume":"14","year":"2021","journal-title":"J Inflamm Res"},{"key":"2026010601500436000_2026.01.02.697430v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2023.08.002"},{"key":"2026010601500436000_2026.01.02.697430v1.37","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-325792"},{"key":"2026010601500436000_2026.01.02.697430v1.38","doi-asserted-by":"crossref","first-page":"1185517","DOI":"10.3389\/fimmu.2023.1185517","article-title":"Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress","volume":"14","year":"2023","journal-title":"Front Immunol"},{"key":"2026010601500436000_2026.01.02.697430v1.39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601540"},{"key":"2026010601500436000_2026.01.02.697430v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2019.09.008"},{"issue":"1","key":"2026010601500436000_2026.01.02.697430v1.41","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1053\/j.gastro.2017.09.019","article-title":"The Function of ATPase Copper Transporter ATP7B in Intestine","volume":"154","year":"2018","journal-title":"Gastroenterology"},{"issue":"1","key":"2026010601500436000_2026.01.02.697430v1.42","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.jcmgh.2021.08.010","article-title":"Chronic Inflammation in Ulcerative Colitis Causes Long-Term Changes in Goblet Cell Function","volume":"13","year":"2022","journal-title":"Cell Mol Gastroenterol Hepatol"},{"issue":"10","key":"2026010601500436000_2026.01.02.697430v1.43","doi-asserted-by":"crossref","first-page":"e0186142","DOI":"10.1371\/journal.pone.0186142","article-title":"Subphenotypes of inflammatory bowel disease are characterized by specific serum protein profiles","volume":"12","year":"2017","journal-title":"PLoS One"},{"key":"2026010601500436000_2026.01.02.697430v1.44","doi-asserted-by":"publisher","DOI":"10.1080\/00365520600554667"},{"key":"2026010601500436000_2026.01.02.697430v1.45","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-011-1936-z"},{"key":"2026010601500436000_2026.01.02.697430v1.46","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2021.07.026"},{"key":"2026010601500436000_2026.01.02.697430v1.47","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/964131"},{"key":"2026010601500436000_2026.01.02.697430v1.48","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0607338"},{"key":"2026010601500436000_2026.01.02.697430v1.49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1005758108"},{"key":"2026010601500436000_2026.01.02.697430v1.50","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2036.2002.01194.x"},{"key":"2026010601500436000_2026.01.02.697430v1.51","doi-asserted-by":"publisher","DOI":"10.1080\/00365520500529470"},{"issue":"12","key":"2026010601500436000_2026.01.02.697430v1.52","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1038\/s41419-018-1223-4","article-title":"Mast cells are essential intermediaries in regulating IL-33\/ST2 signaling for an immune network favorable to mucosal healing in experimentally inflamed colons","volume":"9","year":"2018","journal-title":"Cell Death Dis"},{"issue":"11","key":"2026010601500436000_2026.01.02.697430v1.53","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.tcb.2024.01.004","article-title":"Epithelial metabolism as a rheostat for intestinal inflammation and malignancy","volume":"34","year":"2024","journal-title":"Trends Cell Biol"},{"issue":"7","key":"2026010601500436000_2026.01.02.697430v1.54","first-page":"159528","article-title":"Lipid signature associated with chronic colon inflammation reveals a dysregulation in colonocyte differentiation process","volume":"1869","year":"2024","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"},{"key":"2026010601500436000_2026.01.02.697430v1.55","doi-asserted-by":"crossref","unstructured":"Smith, S.A. , et al., Mitochondrial dysfunction in inflammatory bowel disease alters intestinal epithelial metabolism of hepatic acylcarnitines. J Clin Invest, 2021. 131(1).","DOI":"10.1172\/JCI133371"},{"issue":"1","key":"2026010601500436000_2026.01.02.697430v1.56","doi-asserted-by":"crossref","first-page":"11026","DOI":"10.1038\/s41467-025-65988-2","article-title":"Patient-derived colon epithelial organoids reveal lipid-related metabolic dysfunction in pediatric ulcerative colitis","volume":"16","year":"2025","journal-title":"Nat Commun"},{"key":"2026010601500436000_2026.01.02.697430v1.57","doi-asserted-by":"crossref","unstructured":"Liu, Z. , et al., Dyslipidaemia Is Associated with Severe Disease Activity and Poor Prognosis in Ulcerative Colitis: A Retrospective Cohort Study in China. Nutrients, 2022. 14(15).","DOI":"10.3390\/nu14153040"},{"key":"2026010601500436000_2026.01.02.697430v1.58","first-page":"1198988","article-title":"Association of serum lipids with inflammatory bowel disease: a systematic review and meta-analysis","volume":"10","year":"2023","journal-title":"Front Med (Lausanne)"},{"key":"2026010601500436000_2026.01.02.697430v1.59","doi-asserted-by":"crossref","first-page":"671","DOI":"10.2147\/IJGM.S481323","article-title":"Blood Lipid Levels and Their Value as Markers of Disease Activity in Severe Ulcerative Colitis","volume":"18","year":"2025","journal-title":"Int J Gen Med"},{"key":"2026010601500436000_2026.01.02.697430v1.60","doi-asserted-by":"publisher","DOI":"10.1093\/ecco-jcc\/jjy035"},{"issue":"8","key":"2026010601500436000_2026.01.02.697430v1.61","first-page":"4557","article-title":"A guide to histomorphological evaluation of intestinal inflammation in mouse models","volume":"7","year":"2014","journal-title":"Int J Clin Exp Pathol"},{"key":"2026010601500436000_2026.01.02.697430v1.62","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2026010601500436000_2026.01.02.697430v1.63","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"2026010601500436000_2026.01.02.697430v1.64","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"2026010601500436000_2026.01.02.697430v1.65","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae456"},{"key":"2026010601500436000_2026.01.02.697430v1.66","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2021.04.048"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.01.02.697430","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T09:50:16Z","timestamp":1767693016000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.01.02.697430"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,3]]},"references-count":66,"URL":"https:\/\/doi.org\/10.64898\/2026.01.02.697430","relation":{},"subject":[],"published":{"date-parts":[[2026,1,3]]},"subtype":"preprint"}}