SUMOylation enhances the activity of IDH2 under oxidative stress.
SUMOylation enhances the activity of IDH2 under oxidative stress.
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DOI：
10.1016/j.bbrc.2020.08.089
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发表时间：
2020-09
影响因子：
3.1
通讯作者：
Yun Yu;Yalan Chen;Kexin Liu;Jinke Cheng;Jun Tu
中科院分区：
文献类型：
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作者：
Yun Yu;Yalan Chen;Kexin Liu;Jinke Cheng;Jun Tu
线粒体在生物氧化中起着核心作用，生物氧化不可避免地产生活性氧（ROS）作为副产物。线粒体氧化还原平衡状态的维持需要NADPH，其主要由线粒体基质蛋白异柠檬酸脱氢酶2（IDH 2）产生。IDH 2的活性受翻译后修饰（PTM）调节。在本研究中，我们发现IDH 2在赖氨酸45处被小泛素样修饰物1（SUMO 1）修饰。SUMO特异性蛋白酶1（SENP 1）负责IDH 2的去SUMO化。IDH 2的SUMO化由氧化剂诱导并增强IDH 2的抗氧化活性以保护细胞免受氧化应激。SUMO化位点的突变损害IDH 2的酶活性，从而降低α-酮戊二酸（α-KG）、NADPH和GSH的水平。在氧化应激下，具有SUMO化缺陷型IDH 2的细胞比具有野生型IDH 2的细胞遭受更多的凋亡。这些结果表明SUMO化是调节IDH 2活性以维持线粒体氧化还原平衡的重要途径。
Mitochondria play a central role in biological oxidation that inevitably generates reactive oxygen species (ROS) as by-products. Maintenance of mitochondrial redox balance status requires NADPH, which is primarily generated by the mitochondrial matrix protein isocitrate dehydrogenase 2 (IDH2). The activity of IDH2 is regulated by post-translational modifications (PTMs). In this study, we found IDH2 is modified by small ubiquitin-like modifier 1 (SUMO1) at lysine 45. SUMO specific protease 1 (SENP1) is responsible for deSUMOylation of IDH2. SUMOylation of IDH2 is induced by oxidants and enhances the antioxidant activity of IDH2 to protect cells against oxidative stress. Mutation of the SUMOylation site impairs the enzymatic activity of IDH2 and hence decreases levels of α-ketoglutarate (α-KG), NADPH and GSH. Cells with SUMOylation deficient IDH2 suffer more apoptosis than that with wild type IDH2 under oxidative stress. These results indicate that SUMOylation is an important way to regulate IDH2 activity to maintain mitochondrial redox balance.