精要：

In brief

Different from protein interactions 

mediated by amino acid side chains, the

E3 ligase CUL2FEM1B selectively recruits

the reduced FNIP1 that emerges upon

reductive stress through zinc ions at the

interface of E3 ligase and substrate. This

interaction is gated by pseudosubstrate

inhibitors of the BEX family.

不同于氨基酸侧链介导的蛋白质相互作用，E3泛素连接酶CUL2FEM1B选择性招募还原性FNIP1，通过锌离子与E3泛素连接酶的结合和底物相互作用来上调还原性应激反应。这一相互作用过程被BEX家族的假底物抑制剂所调控。

SUMMARY

概要

Although oxidative phosphorylation（氧化磷酸化） is best known for producing ATP, it also yields reactive oxygen species(ROS) as invariant byproducts. Depletion of ROS below their physiological levels, a phenomenon known as reductive stress, impedes cellular signaling and has been linked to cancer, diabetes, and cardiomyopathy.Cells alleviate reductive stress by ubiquitylating and degrading the mitochondrial gatekeeper FNIP1, yet it is unknown how the responsible E3 ligase CUL2FEM1B can bind its target based on redox state and how this is adjusted to changing cellular environments. Here, we show that CUL2FEM1B relies on zinc as a molecular glue to selectively recruit reduced FNIP1 during reductive stress. 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-dependent reductive stress response must be tightly regulated to maintain cellular and organismal homeostasis.

虽然氧化磷酸化是产生ATP的经典通路，但同时也伴随着活性氧的产生。当活性氧的清除低于生理水平时，就会产生还原性应激反应，阻碍细胞信号传导，并且与癌症，糖尿病，心肌病相关。细胞听过泛素化和降解线粒体看守蛋白FNIP1来减轻还原性应激，但目前不清楚E3泛素连接酶CUL2FEM1B是如何根据氧化还原状态结合它的靶标，并且如何适应细胞环境的变化。我们发现CUL2FEM1B通过结合分子胶水锌离子，去选择性招募在还原性应激中的FNIP1。FNIP1的泛素化被BEX家族这类假底物抑制剂所把控，这一过程是防止FNIP1过早的降解，保护细胞免受活性氧积聚的损伤。FEM1B的获得性突变和BEX的缺失引起类似的进行性神经综合征，表明锌离子依赖的还原性应激反应必须被严格调节，以维持细胞和有机体稳态

（from：https://doi.org/10.1016/j.cell.2021.09.002）

一些反思：

这个周好像没有做什么事情，实验进度总体1%？

昨天真的起的有点晚，耽误了师姐进细胞房的时间，心里觉得好罪过

哭泣(ㄒoㄒ)