TRANSFER RNA MODIFICATION CONTRIBUTE TO PATHOGENESIS OF INTESTINAL INFLAMMATION BY ALTERING EPITHELIAL BARRIERS

Abstract BACKGROUNDS Transfer RNA (tRNA) is the most extensively modified in cells. Queuosine (Q)-modification a fundamental process for fidelity and efficiency of translation from to proteins. In eukaryotes, tRNA-Q-modification relies on intestinal microbial product queuine. Growing evidence indicates that tRNA modifications play important roles human diseases, e.g., type 2 diabetes. Q depletion led endoplasmic reticulum stress mouse liver. Q-tRNA are dynamic highly variable depending developmental stages species tumorigenesis. However, health consequences disturbed availability queuine altered modification remain be investigated. The effects mechanisms bowel diseases (IBD) unknown. METHODS We explored Q-tRNA-related synthetases expression ribosyltransferase catalytic subunit 1 (QTRT1) patients with IBD by investigating biopsies reanalyzing datasets. used several colitis models, organoids, cultured cells loss- gain-of-function studies investigate barrier functions, proliferation, inflammation. RESULTS ulcerative Crohn’s disease patients, QTRT1 was significantly downregulated. Altered QTRT1-related metabolites were found IBD. four synthetases, asparaginyl-aspartyl-, histidyl-, tyrosyl-tRNA synthetase, decreased patients. This reduction further confirmed DSS-induced IL10-deficient mice. Reduced correlated junctions, including downregulated β-catenin upregulated Claudin-2. These alterations vitro deleting Queuine treatment enhanced cell junctional functions reduced inflammation epithelial CONCLUSION an unexplored novel role pathogenesis altering barriers. Insights into regulating would facilitate development targeted interventions through modifications.