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A Cellular Mechanism to Detect and Alleviate Reductive Stress.
Cell ( IF 64.5 ) Pub Date : 2020-09-16 , DOI: 10.1016/j.cell.2020.08.034
Andrew G Manford 1 , Fernando Rodríguez-Pérez 2 , Karen Y Shih 2 , Zhuo Shi 1 , Charles A Berdan 3 , Mangyu Choe 4 , Denis V Titov 4 , Daniel K Nomura 5 , Michael Rape 6
Affiliation  

Metazoan organisms rely on conserved stress response pathways to alleviate adverse conditions and preserve cellular integrity. Stress responses are particularly important in stem cells that provide lifetime support for tissue formation and repair, but how these protective systems are integrated into developmental programs is poorly understood. Here we used myoblast differentiation to identify the E3 ligase CUL2FEM1B and its substrate FNIP1 as core components of the reductive stress response. Reductive stress, as caused by prolonged antioxidant signaling or mitochondrial inactivity, reverts the oxidation of invariant Cys residues in FNIP1 and allows CUL2FEM1B to recognize its target. The ensuing proteasomal degradation of FNIP1 restores mitochondrial activity to preserve redox homeostasis and stem cell integrity. The reductive stress response is therefore built around a ubiquitin-dependent rheostat that tunes mitochondrial activity to redox needs and implicates metabolic control in coordination of stress and developmental signaling.



中文翻译:

检测和缓解还原应激的细胞机制。

后生动物依靠保守的应激反应途径来缓解不利条件并保持细胞完整性。应激反应对于为组织形成和修复提供终生支持的干细胞尤其重要,但人们对这些保护系统如何整合到发育程序中知之甚少。在这里,我们利用成肌细胞分化来鉴定 E3 连接酶 CUL2 FEM1B及其底物 FNIP1 作为还原应激反应的核心成分。由延长的抗氧化信号传导或线粒体不活动引起的还原应激可恢复 FNIP1 中不变的 Cys 残基的氧化,并使 CUL2 FEM1B能够识别其靶标。随后的 FNIP1 蛋白酶体降解可恢复线粒体活性,以保持氧化还原稳态和干细胞完整性。因此,还原应激反应是围绕泛素依赖性变阻器构建的,该变阻器根据氧化还原需求调节线粒体活性,并暗示协调应激和发育信号传导的代谢控制。

更新日期:2020-10-02
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