Maintenance of intestinal homeostasis by deubiquitinase PTUD3

为了评估OTUD3在肠道中的生理功能，我们采用基因靶向的方法培养了OTUD3缺陷小鼠。我们观察到缺陷小鼠在服用DSS期间表现出更严重的结肠炎。在小鼠结肠中，otud3mrna在成纤维细胞中相对于上皮细胞、先天免疫细胞和适应性免疫细胞高表达。成纤维细胞中Otud3缺乏导致结肠炎的加重。通过对结肠成纤维细胞进行scRNA-seq分析，我们发现dotud3在结肠成纤维细胞的一个特殊亚群中调节STING-IFN信号通路。通过使用抗生素（ABX）处理和无菌小鼠，我们发现OTUD3调节结肠成纤维细胞的微生物cGAMP-STING-IFN通路。我们产生了OTUD3 UC风险变异小鼠的敲入菌株，并证实OTUD3中的UC风险变异与肠成纤维细胞中STING激活失调有关。现在我正准备把论文投给一个重要的学术期刊。成纤维细胞是最丰富的结构细胞，发挥体内平衡功能，但也驱动疾病的发病机制。单细胞技术揭示了多种疾病中致病性成纤维细胞的共同特征。然而，疾病相关成纤维细胞表型的分子机制仍不清楚。我们的发现为致病性成纤维细胞极化提供了机制基础，并具有重要的治疗意义

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