Maintenance of intestinal homeostasis by deubiquitinase PTUD3

去泛素酶 PTUD3 维持肠道稳态

• 批准号: 21F21112
• 负责人: 竹田 潔
• 金额: $ 1.47万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2021
• 资助国家: 日本
• 起止时间: 2021-04-28 至 2023-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21F21112/
• 关键词: intestine stromal cell; ubiquitination; intestine; stromal cell

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

为了评估OTUD 3在肠道中的生理功能，我们通过使用基因靶向产生Otud 3缺陷小鼠。在小鼠结肠中，Otud 3 mRNA在成纤维细胞中的表达高于上皮细胞、先天性免疫细胞和适应性免疫细胞。成纤维细胞中Otud 3缺陷导致结肠炎加重。通过使用结肠成纤维细胞进行scRNA-seq分析，我们发现OTUD 3在结肠成纤维细胞的特殊亚群中调节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OTUD 3在结肠成纤维细胞中调节微生物cGAMP-STING-IFN通路。我们产生了OTUD 3 UC风险变异小鼠的敲入品系，并证实了OTUD 3中的这种UC风险变体与肠道成纤维细胞中STING激活的失调有关。现在我正准备将论文提交给一个主要的学术期刊。成纤维细胞是最丰富的结构细胞，发挥稳态功能，但也驱动疾病的发病机制。单细胞技术已经阐明了多种疾病中致病成纤维细胞的共同特征。然而，疾病相关的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

项目成果

The ATP-hydrolyzing ectoenzyme E-NTPD8 attenuates colitis through modulation of P2X4 receptor-dependent metabolism in myeloid cells.

• DOI: 10.1073/pnas.2100594118
• 发表时间: 2021-09-28
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Tani H;Li B;Kusu T;Okumura R;Nishimura J;Okuzaki D;Motooka D;Arakawa S;Mori A;Yoshihara T;Ogino T;Tsai SH;Furuta Y;Muneta M;Nakamura S;Fukusaki E;Yamamoto K;Yagita H;Kayama H;Takeda K
• 通讯作者: Takeda K

潰瘍性大腸炎感受性遺伝子OTUD3による腸管恒常性維持機構

溃疡性结肠炎易感基因OTUD3维持肠道稳态的机制

• 发表时间: 2021
• 作者: 香山尚子;竹田潔
• 通讯作者: 竹田潔

Deubiquitinase OTUD3 prevents colitis by modulating microbiota-dependent STING activation in PDGFRα+ stromal cells

去泛素酶 OTUD3 通过调节 PDGFRα+ 基质细胞中微生物群依赖性 STING 激活来预防结肠炎

• 发表时间: 2022
• 作者: Chao Y;Luo Y;Owusu Mensah RNA;Zhang J;Sugihara I;Bo Li
• 通讯作者: Bo Li