Maintenance of intestinal homeostasis by deubiquitinase PTUD3

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To assess the physiological function of OTUD3 in the intestine, we generated Otud3 deficient mice by using gene targeting. We observed that deficient mice exhibited more severe colitis during DSS administration.In murine colon, Otud3 mRNA was highly expressed in fibroblasts relative to epithelia cells and innate and adaptive immune cells. Otud3 deficiency in fibroblasts leads to aggravation of colitis.By performing scRNA-seq analysis using colonic fibroblasts, we foundOTUD3 modulates the STING-IFN signaling pathway in a special subset of colonic fibroblasts.By making use of antibiotics (ABX) treatment and germ free mice, we found OTUD3 modulates the microbial cGAMP-STING-IFN pathway in colonic fibroblasts.We generated a knock-in strain of OTUD3 UC risk variant mice, and confirmed this UC risk variant in OTUD3 is associated with dysregulation of STING activation in intestinal fibroblasts.Now I am preparing to submit the paper to a major acdemic journal.Fibroblasts, the most abundant structural cells, exert homeostatic functions but also drive disease pathogenesis. Single-cell technologies have illuminated the shared characteristics of pathogenic fibroblasts in multiple diseases. However, the molecular mechanisms underlying the disease-associated fibroblast phenotypes remain largely unclear. Our findings provide a mechanistic basis for pathogenic fibroblast polarization and have important therapeutic implications