Loss of E3 ligase Ube4A Disrupts Colon Homeostasis and Accelerates Experimental Colitis via Altered Lipid Handling.

Background: Ubiquitin-dependent signaling is essential for maintaining intestinal homeostasis and its dysregulation contributes to chronic intestinal disorders, such as Inflammatory Bowel Disease (IBD). Ube4A is a U-box E3/E4 ubiquitin ligase involved in lipid metabolism and insulin signaling in metabolic tissues. Autoantibodies against Ube4A have been identified in patients with IBD and are associated with disease long-term complications. Despite these clinical associations, the physiological role of Ube4A in the gastrointestinal tract remains unknown. This study aimed to define the function of Ube4A in the colon and determine how its loss influences susceptibility to experimental colitis. Methods: UBE4A expression in human colonic tissue from healthy individuals and patients with IBD was analyzed using publicly available single-cell RNA sequencing datasets. The role of Ube4A in colonic homeostasis and colitis pathogenesis was examined using global Ube4A knockout (UKO) mice subjected to dextran sulfate sodium (DSS)-induced colitis. UKO colon phenotypes were characterized using transcriptomic analyses, immunofluorescence, and flow cytometry. Results: UBE4A is highly expressed in human colonic epithelial cells, and its expression is reduced from healthy to IBD inflamed tissues. In mice, Ube4A deficiency significantly exacerbated DSS-induced colitis, as evidenced by increased weight loss, disease activity scores, shortened colon length, and more severe histological injury. Transcriptomic profiling revealed enhanced inflammatory signaling, alongside dysregulation of lipid transport and storage, as well as antimicrobial defense pathways. DSS-treated UKO mice also exhibited increased mast cell activation and elevated expression of matrix metalloproteinases. Importantly, colons from UKO mice displayed baseline transcriptional alterations indicative of epithelial stress and disrupted lipid metabolic programs, even in the absence of injury. Conclusions: Ube4A is a previously unrecognized regulator of colon homeostasis. Its loss induces existing epithelial stress and metabolic reprogramming that sensitize the colon to exaggerated inflammatory responses during injury such as experimental colitis.