UC San Diego

Inflammatory Bower Disease (IBD) is composed of ulcerative colitis (UC) and Crohn's disease (CD). Both genetic and environmental factors contribute to this pathogenesis, which has a common feature of compromised intestinal epithelial barrier in the small and large intestines. We investigated the role of STAT3 in intestinal epithelial cells (STAT3IEC) and identified a novel function of STAT3 in maintaining intestinal homeostasis. STAT3IEC deletion in mice resulted in compromised barrier function and the loss of IEC polarity due to low tight junction protein levels (i.e. claudin-1, -3, and -5) in vitro and in vivo. We further identified that STAT3 maintains tight junction protein level in vitro and in vivo by inducing ubiquitin- mediated degradation of SNAI, a transcriptional suppressor of claudins. STAT3 binds with GSK3b, which phosphorylates SNAI for ubiquination and results in degradation. Moreover, STAT3 is essential for host defense against enteropathogenic bacteria (i.e. Citrobacter rodentium and E.coli). STAT3IEC knock out mice are highly susceptible to C. rodentium infection due to impaired IEC barrier and antimicrobial peptide (i.e. regIIIg) induction, which is necessary for bacterial clearance. Collectively, STAT3 along with GSK3b forms a SNAI destruction complex in IECs to maintain claudin levels and thus results in proper barrier function and antibacterial defense