Oxidative stress promotes fibrosis in systemic sclerosis through stabilization of a kinase-phosphatase complex.
Oxidative stress promotes fibrosis in systemic sclerosis through stabilization of a kinase-phosphatase complex.
复制标题
氧化应激通过稳定激酶-磷酸酶复合物促进系统性硬化症的纤维化
DOI：
10.1172/jci.insight.155761
复制
发表时间：
2022-04-22
期刊：
影响因子：
8
通讯作者：
Bottini, Nunzio
中科院分区：
文献类型：
--
作者：
Zhang, Ruiyuan;Kumar, Ganesan Senthil;Hansen, Uwe;Zoccheddu, Martina;Sacchetti, Cristiano;Holmes, Zachary J.;Lee, Megan C.;Beckmann, Denise;Wen, Yutao;Mikulski, Zbigniew;Yang, Shen;Santelli, Eugenio;Page, Rebecca;Boin, Francesco;Peti, Wolfgang;Bottini, Nunzio
系统性硬化症（SSc）是一种以局部氧化应激增强成纤维细胞的致病性激活为特征的纤维化自身免疫性疾病。酪氨酸磷酸酶PTP4A1被鉴定为SSc中TGF-β信号传导的关键启动子。众所周知，氧化应激可使酪氨酸磷酸酶在功能上失活。在这里，我们评估了PTP4A1的氧化是否调节其促纤维化作用，并发现PTP4A1在硬皮病成纤维细胞中与激酶SRC形成复合物，但令人惊讶的是，氧化应激增强而不是降低PTP4A1与SRC的关联及其促纤维化作用。通过对oxo-PTP4A1-SRC复合物的结构评估，我们揭示了一种意想不到的机制，即酪氨酸磷酸酶的氧化通过修饰其蛋白质复合物来促进其功能。考虑到氧化应激在SSc和纤维化发病机制中的重要性，我们的研究结果提示利用PTP4A1氧化作为开发抗纤维化药物的潜在策略。
Systemic sclerosis (SSc) is a fibrotic autoimmune disease characterized by pathogenic activation of fibroblasts enhanced by local oxidative stress. The tyrosine phosphatase PTP4A1 was identified as a critical promoter of TGF-β signaling in SSc. Oxidative stress is known to functionally inactivate tyrosine phosphatases. Here, we assessed whether oxidation of PTP4A1 modulates its profibrotic action and found that PTP4A1 forms a complex with the kinase SRC in scleroderma fibroblasts, but surprisingly, oxidative stress enhanced rather than reduced PTP4A1’s association with SRC and its profibrotic action. Through structural assessment of the oxo-PTP4A1-SRC complex, we unraveled an unexpected mechanism whereby oxidation of a tyrosine phosphatase promotes its function through modification of its protein complex. Considering the importance of oxidative stress in the pathogenesis of SSc and fibrosis, our findings suggest routes for leveraging PTP4A1 oxidation as a potential strategy for developing antifibrotic agents.
登录
查看更多内容
影响因子：
2.9
作者：
Banavali, Nilesh K.;Roux, Benoit
通讯作者：
Roux, Benoit
影响因子：
8
作者：
Hardy, S.;Uetani, N.;Tremblay, M. L.
通讯作者：
Tremblay, M. L.
DOI：
10.1007/s10969-007-9036-1
发表时间：
2007-09-01
期刊：
Journal of Structural and Functional Genomics
影响因子：
--
作者：
Almo, Steven C.;Bonanno, Jeffrey B.;Burley, Stephen K.
通讯作者：
Burley, Stephen K.
影响因子：
16.6
作者：
Chakraborty D;Šumová B;Mallano T;Chen CW;Distler A;Bergmann C;Ludolph I;Horch RE;Gelse K;Ramming A;Distler O;Schett G;Šenolt L;Distler JHW
通讯作者：
Distler JHW
DOI：
10.1002/art.39242
发表时间：
2015-10
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Piera-Velazquez S;Makul A;Jiménez SA
通讯作者：
Jiménez SA