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Compound exocytosis enables the rapid, high\u2010volume release of mucus from goblet cells; its underlying mechanisms, however, remain unclear. Here, death receptor 5 (DR5) is identified as a critical regulator of this process. Knockout of\n                    <jats:italic>DR5<\/jats:italic>\n                    exhibits a thinner mucus layer despite elevated Muc2 and enlarged granules, causing mild dysbiosis and enhances susceptibility to\n                    <jats:italic>Citrobacter rodentium<\/jats:italic>\n                    .\n                    <jats:italic>DR5<\/jats:italic>\n                    knockout and its ligand\n                    <jats:italic>TRAIL<\/jats:italic>\n                    knockdown inhibits carbachol\u2010triggered goblet cell compound exocytosis, while DR5\u2010activator Bioymifi potentiates it. DR5 modulates intracellular pH through the colonic goblet cell\u2010expressed HCO\n                    <jats:sub>3<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    channel Bestrophin\u20102 (Best2). TRAIL\/DR5\/Best2 co\u2010localize in goblet cells, and\n                    <jats:italic>Best2<\/jats:italic>\n                    knockdown abolishes DR5's pro\u2010exocytosis effect. Proteomics and bioinformatic analyses implicate TATA\u2010box binding protein (TBP) in the death domain\u2010dependent transcriptional regulation of\n                    <jats:italic>Best2<\/jats:italic>\n                    by DR5. This is supported by TBP\u2010\n                    <jats:italic>BEST2<\/jats:italic>\n                    promoter binding, as well as enhanced\n                    <jats:italic>BEST2<\/jats:italic>\n                    mRNA expression and promoter activity upon\n                    <jats:italic>TBP<\/jats:italic>\n                    overexpression.\n                    <jats:italic>DR5<\/jats:italic>\n                    knockout suppresses TBP expression in colonic goblet cells, while activation increases it. Moreover,\n                    <jats:italic>TBP<\/jats:italic>\n                    knockdown abrogates Bioymifi\u2010enhanced Best2 expression and compound exocytosis. The findings demonstrate that disruption of the DR5\u2010TBP\u2010Best2 axis in goblet cells perturbs goblet cell compound exocytosis and mucus layer formation, resulting in dysbiosis and heightened infection susceptibility.\n                  <\/jats:p>","DOI":"10.1002\/advs.202516789","type":"journal-article","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T08:57:25Z","timestamp":1762851445000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["DR5 Governs Compound Exocytosis in Colonic Goblet Cells via TATA\u2010Box Binding Protein\u2010Dependent Bestrophin\u20102 Transcriptional Regulation"],"prefix":"10.1002","volume":"13","author":[{"given":"Ying","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathophysiology School of Basic Medical Science Cheeloo College of Medicine Shandong University Jinan 250012 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