Oxidative Stress Impairs Cell Death by Repressing the Nuclease Activity of Mitochondrial Endonuclease G.
Oxidative Stress Impairs Cell Death by Repressing the Nuclease Activity of Mitochondrial Endonuclease G.
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DOI：
10.1016/j.celrep.2016.05.090
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发表时间：
2016-07-12
期刊：
影响因子：
8.8
通讯作者：
Yuan HS
中科院分区：
文献类型：
--
作者：
Lin JLJ;Nakagawa A;Skeen-Gaar R;Yang WZ;Zhao P;Zhang Z;Ge X;Mitani S;Xue D;Yuan HS
内切酶G （EndoG）是一种线粒体蛋白，在细胞凋亡过程中从线粒体释放并重新定位到细胞核中以促进染色体DNA的断裂。在这里，我们表明氧化应激通过内啡肽介导的细胞死亡途径导致秀丽隐杆线虫的细胞死亡缺陷。在高ROS水平下，同型二聚体cps -6（线虫内酯的同源物）被解离成核酸酶活性降低的单体。相反，CPS-6的核酸酶活性增强，其二聚体结构稳定，通过与蠕虫AIF同源物WAH-1的相互作用，在高ROS水平下转变为二硫交联二聚体。因此，CPS-6在作为ROS传感器调节细胞的生死方面发挥了意想不到的作用。调节EndoG二聚体构象可以为预防和治疗氧化应激引起的疾病提供一条途径。
Endonuclease G (EndoG) is a mitochondrial protein that is released from mitochondria and relocated into the nucleus to promote chromosomal DNA fragmentation during apoptosis. Here, we show that oxidative stress causes cell death defects in C. elegans through an EndoG-mediated cell death pathway. In response to high ROS levels, homodimeric CPS-6—the C. elegans homolog of EndoG—is dissociated into monomers with diminished nuclease activity. Conversely, the nuclease activity of CPS-6 is enhanced and its dimeric structure is stabilized by its interaction with the worm AIF homolog, WAH-1, which shifts to disulfide cross-linked dimers under high ROS levels. CPS-6 thus plays an unexpected role in acting as a ROS sensor to regulate the life and death of cells. Modulation of the EndoG dimer conformation could present an avenue for prevention and treatment of diseases resulting from oxidative stress.