Loss of TRIM68 in intestinal epithelial cells exacerbates colitis via TAB2 ubiquitination 2305968

Abstract

Abstract Introduction Inflammatory bowel diseases (IBDs) are becoming an increasingly significant public health problem, with roughly 1 in 100 Americans currently affected. Intestinal epithelial cells (IECs) serve as the first line of defense against intestinal pathogens and play a pivotal role in the initiation of colitis. TRIM68, an E3 ligase, is highly expressed in IECs, but its function in intestinal inflammation remains unclear. Methods To investigate its role, we specifically generate TRIM68 totally knockout (Trim68-/-) and IEC conditionally knockout (Trim68IEC-KO) mice. Colitis was induced using dextran sodium sulfate (DSS), and disease severity was evaluated through body weight changes, histopathological scoring, and cytokine expression analysis. Results Following dextran sodium sulfate (DSS) administration, TRIM68-deficient mice exhibited pronounced body weight loss, more severe histopathological damage, and elevated IL-6 and IL-1β expression compared with control mice. Notably, Trim68IEC-KO mice exhibited almost identical responses to Trim68-/- mice, highlighting the essential contribution of IEC expressed TRIM68. Mechanistically, TRIM68 binds to TGF-β—activated kinase 1—binding protein 2 (TAB2), an essential upstream adaptor of NF-κB signaling responsible for inducing IL-6 and IL-1β. This interaction promotes ubiquitination and degradation of TAB2, thereby dampening downstream proinflammatory cytokine induction. Conclusion Our findings reveal that TRIM68 acts as a novel negative regulator in the host innate immune response to colitis specifically within IECs. These results expand the understanding of colitis pathogenesis and suggest TRIM68 as a potential therapeutic target. Funding Source 1R56AI148215, R01AI155488 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)