CBP phosphorylation maintains intestinal homeostasis by supporting the stem cell niche through versican

CREB-binding protein (CBP) is a transcriptional coactivator, and we reported its phosphorylation regulates cell fate. Impaired CBP phosphorylation alters its binding preference for p53 in CBP^AA mice, leading to distal colonic abnormalities. These changes are accompanied by reduced expression of versican, an extracellular matrix component that supports the intestinal stem cell niche, leading to impaired intestinal epithelial cell (IEC) proliferation and organoid formation. Deleting p53 in the IECs of CBP^AA mice (CBP^AAp53^ΔIEC) restores versican expression and reverses the colonic phenotype. Versican replenishment and phosphomimetic CBP mutants rescue versican expression and IEC stemness in CBP^AA organoids. Importantly, colonic tissues from ulcerative colitis patients exhibit impaired CBP phosphorylation, increased CBP-p53 binding, decreased versican expression and IEC proliferation, highlighting the clinical relevance of this phenomenon. In this work, we demonstrate CBP phosphorylation safeguards intestinal homeostasis by maintaining the stem cell niche through versican, highlighting versican as a potential therapeutic target for inflammatory bowel disease.