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研究揭示还原性应激反应的结构基础和调节机制
作者:小柯机器人 发布时间:2021/9/30 10:42:08

美国加州大学伯克利分校Michael Rape团队揭示还原性应激反应的结构基础和调节机制。相关论文于2021年9月24日在线发表在《细胞》杂志上。

研究人员表示,尽管氧化磷酸化以产生ATP而闻名,但它也会产生活性氧(ROS)作为恒定的副产品。ROS的消耗低于其生理水平,这种现象被称为还原性压力,会阻碍细胞的信号传递,并与癌症、糖尿病和心肌病有关。细胞通过泛素化和降解线粒体蛋白FNIP1来缓解还原性应激,但负责的E3连接酶CUL2FEM1B如何根据氧化还原状态结合其目标,以及如何根据变化的细胞环境进行调整,目前还不清楚。

研究人员发现,CUL2FEM1B依靠锌作为分子胶水,在还原性压力期间选择性地招募减少的FNIP1。FNIP1泛素化被BEX家族的假底物抑制剂所控制,它防止FNIP1过早降解,进而保护细胞免受不必要的ROS积累。FEM1B功能获得性突变和BEX缺失引起类似的发育综合征,这表明锌依赖的还原性应激反应必须受到严格的调节来维持细胞和机体的平衡。

附:英文原文

Title: Structural basis and regulation of the reductive stress response

Author: Andrew G. Manford, Elijah L. Mena, Karen Y. Shih, Christine L. Gee, Rachael McMinimy, Brenda Martínez-González, Rumi Sherriff, Brandon Lew, Madeline Zoltek, Fernando Rodríguez-Pérez, Makda Woldesenbet, John Kuriyan, Michael Rape

Issue&Volume: 2021-09-24

Abstract: Although oxidative phosphorylation is best known for producing ATP, it also yieldsreactive oxygen species (ROS) as invariant byproducts. Depletion of ROS below theirphysiological levels, a phenomenon known as reductive stress, impedes cellular signalingand has been linked to cancer, diabetes, and cardiomyopathy. Cells alleviate reductivestress by ubiquitylating and degrading the mitochondrial gatekeeper FNIP1, yet itis unknown how the responsible E3 ligase CUL2FEM1B can bind its target based on redox state and how this is adjusted to changing cellularenvironments. Here, we show that CUL2FEM1B relies on zinc as a molecular glue to selectively recruit reduced FNIP1 during reductivestress. FNIP1 ubiquitylation is gated by pseudosubstrate inhibitors of the BEX family,which prevent premature FNIP1 degradation to protect cells from unwarranted ROS accumulation.FEM1B gain-of-function mutation and BEX deletion elicit similar developmental syndromes, showing that the zinc-dependentreductive stress response must be tightly regulated to maintain cellular and organismalhomeostasis.

DOI: 10.1016/j.cell.2021.09.002

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01049-7

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/