FUS interacts with ATP synthase beta subunit and induces mitochondrial unfolded protein response in cellular and animal models
FUS interacts with ATP synthase beta subunit and induces mitochondrial unfolded protein response in cellular and animal models
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FUS 与 ATP 合酶 β 亚基相互作用并在细胞和动物模型中诱导线粒体未折叠蛋白反应
DOI：
10.1073/pnas.1806655115
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发表时间：
2018-10-09
影响因子：
11.1
通讯作者：
Wu, Jane Y.
中科院分区：
文献类型：
--
作者：
Deng, Jianwen;Wang, Peng;Wu, Jane Y.
在这项研究中，我们使用了FUS蛋白病的诱导细胞模型来证明线粒体功能障碍是FUS引起的最早可检测到的变化。在细胞和果蝇模型中，FUS与线粒体ATP合成酶β-亚基（ATP5B）相互作用，破坏ATP合成酶复合物的组装，抑制线粒体ATP合成酶的活性，激活线粒体未折叠蛋白反应（UPRmt）。ATP5B在表达FUS的细胞和果蝇中表达增加。下调ATP5B或UPRmt基因的表达可改善fus诱导的神经变性。我们的数据揭示了FUS在靶向线粒体ATP合成和激活UPRmt中的先前未知的作用。FUS（融合肉瘤）蛋白病是一组以形成含有FUS蛋白的包涵体为特征的神经退行性疾病，包括额颞叶变性和肌萎缩性侧索硬化症。以往的研究表明，线粒体损伤是FUS蛋白病的一个重要方面。然而，FUS诱导线粒体损伤的分子机制仍有待阐明。我们的生化和遗传学实验表明，FUS与线粒体ATP合成酶（ATP5B）的催化亚基相互作用，破坏ATP合成酶复合物的形成，抑制线粒体ATP合成。FUS表达激活线粒体未折叠蛋白反应（UPRmt）。重要的是，在FUS转基因果蝇中下调ATP5B或UPRmt基因的表达可改善神经退行性表型。我们的数据表明，线粒体损伤是FUS蛋白病的关键早期事件，并为FUS诱导的神经变性的致病机制提供了见解。
Significance In this study, we used an inducible cellular model for FUS proteinopathy to demonstrate that mitochondrial dysfunction occurs as the earliest detectable change induced by FUS. In cellular and fly models, FUS interacts with the mitochondrial ATP synthase β-subunit (ATP5B), disrupts ATP synthase complex assembly, suppresses the activity of mitochondrial ATP synthase, and activates the mitochondrial unfolded protein response (UPRmt). ATP5B expression is increased in cells and flies expressing FUS. Down-regulating expression of ATP5B or UPRmt genes ameliorates FUS-induced neurodegeneration. Our data uncover a previously unknown role of FUS in targeting mitochondrial ATP synthesis and activating UPRmt. FUS (fused in sarcoma) proteinopathy is a group of neurodegenerative diseases characterized by the formation of inclusion bodies containing the FUS protein, including frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Previous studies show that mitochondrial damage is an important aspect of FUS proteinopathy. However, the molecular mechanisms by which FUS induces mitochondrial damage remain to be elucidated. Our biochemical and genetic experiments demonstrate that FUS interacts with the catalytic subunit of mitochondrial ATP synthase (ATP5B), disrupts the formation of ATP synthase complexes, and inhibits mitochondrial ATP synthesis. FUS expression activates the mitochondrial unfolded protein response (UPRmt). Importantly, down-regulating expression of ATP5B or UPRmt genes in FUS transgenic flies ameliorates neurodegenerative phenotypes. Our data show that mitochondrial impairment is a critical early event in FUS proteinopathy, and provide insights into the pathogenic mechanism of FUS-induced neurodegeneration.