The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy
The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy
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DOI：
10.1038/nature13418
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发表时间：
2014-06-19
期刊：
影响因子：
64.8
通讯作者：
Sheng, Morgan
中科院分区：
文献类型：
--
作者：
Bingol, Baris;Tea, Joy S.;Sheng, Morgan
细胞通过线粒体自噬降解受损的线粒体来维持健康的线粒体;有缺陷的线粒体自噬与帕金森病有关。在这里，我们报告说，USP 30，一种定位于线粒体的去泛素化酶，拮抗由泛素连接酶parkin（也称为PARK 2）和蛋白激酶PINK 1驱动的线粒体自噬，这两种蛋白激酶由与帕金森病相关的两个基因编码。帕金泛素化和标记受损的线粒体进行清除。USP 30的过表达去除了由parkin附着在受损线粒体上的泛素，并阻断了parkin驱动线粒体自噬的能力，而降低USP 30活性增强了神经元中的线粒体降解。全球泛素化位点分析确定了多个线粒体底物相反帕金和USP 30调节。USP 30的敲除挽救了由parkin致病性突变引起的线粒体自噬缺陷，并改善了parkin或PINK 1缺陷果蝇的线粒体完整性。多巴胺能神经元中USP 30的敲低保护果蝇免受体内百草枯毒性，改善多巴胺水平，运动功能和生物体存活的缺陷。因此，USP 30抑制通过促进线粒体清除和质量控制而对帕金森病潜在有益。
Cells maintain healthy mitochondria by degrading damaged mitochondria through mitophagy; defective mitophagy is linked to Parkinson's disease. Here we report that USP30, a deubiquitinase localized to mitochondria, antagonizes mitophagy driven by the ubiquitin ligase parkin (also known as PARK2) and protein kinase PINK1, which are encoded by two genes associated with Parkinson's disease. Parkin ubiquitinates and tags damaged mitochondria for clearance. Overexpression of USP 30 removes ubiquitin attached by parkin onto damaged mitochondria and blocks parkin's ability to drive mitophagy, whereas reducing USP30 activity enhances mitochondrial degradation in neurons. Global ubiquitination site profiling identified multiple mitochondrial substrates oppositely regulated by parkin and USP30. Knockdown of USP30 rescues the defective mitophagy caused by pathogenic mutations in parkin and improves mitochondrial integrity in parkin-or PINK1-deficient flies. Knockdown of USP30 in dopaminergic neurons protects flies against paraquat toxicity in vivo, ameliorating defects in dopamine levels, motor function and organismal survival. Thus USP30 inhibition is potentially beneficial for Parkinson's disease by promoting mitochondrial clearance and quality control.