Potassium Channel Tetramerization Domain-Containing 10 Modulates Dextran Sodium Sulfate-Induced Ulcerative Colitis...

The incidence of inflammatory bowel disease (IBD) continues to increase annually, which severely threatens public health. Although estimates indicate that current therapies cause a 30% IBD clinical treatment failure, the precise pathogenesis remains unclear. Here, it was found that a key embryonic development regulator, potassium channel tetramerization domain-containing 10 (KCTD10), is correlated with the severity of IBD. Enhanced KCTD10 expression was observed during enterocolitis. Intestinal epithelial cell-specific knockout of KCTD10 in mice impaired intestinal epithelial barrier function, activated intestinal adaptive immune response, and disrupted intestinal homeostasis. Furthermore, in a dextran sodium sulfate-induced ulcerative colitis model, intestinal epithelial cell deletion of KCTD10 exacerbated colonic inflammation and impaired postinjury repair. Mechanistically, KCTD10 deletion down-regulated intestinal stem cell marker genes and affected their function. Importantly, KCTD10 stabilizes the transcription factor ATOH1 by regulating its ubiquitination, thereby determining the fate of intestinal progenitor cells derived from leucine-rich repeat-containing G-protein-coupled receptor 5⁺ intestinal stem cells. The data thus revealed a previously undescribed function of KCTD10 in modulating ulcerative colitis by regulating intestinal stem cell function.