The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy
The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy
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DOI：
10.1093/hmg/ddu244
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发表时间：
2014-10-01
影响因子：
3.5
通讯作者：
Vandenberghe, Wim
中科院分区：
文献类型：
--
作者：
Cornelissen, Tom;Haddad, Dominik;Vandenberghe, Wim
编码E3泛素连接酶Parkin的基因PARK 2的功能缺失突变是隐性帕金森病（PD）的最常见原因。帕金从细胞质易位到去极化的线粒体，泛素化线粒体外膜蛋白，并诱导受损线粒体的选择性自噬（线粒体自噬）。在这里，我们表明，泛素特异性蛋白酶15（USP 15），一种广泛表达于大脑和其他器官的去泛素化酶（DUB），反对帕金森介导的线粒体自噬，而一组其他DUB和催化失活版本的USP 15不。此外，USP 15的敲低挽救了具有PARK 2突变和降低的Parkin水平的PD患者成纤维细胞的线粒体自噬缺陷。USP 15不影响Parkin的泛素化状态或Parkin易位到线粒体，但抵消Parkin介导的线粒体！泛素化DUB CG 8334是果蝇中与USP 15最接近的同源物，它的敲低在很大程度上挽救了parkin RNAi果蝇的线粒体和行为缺陷。这些数据将USP 15鉴定为Parkin拮抗剂，并表明USP 15抑制可能是Parkin水平降低引起的PD病例的治疗策略。
Loss-of-function mutations in PARK2, the gene encoding the E3 ubiquitin ligase Parkin, are the most frequent cause of recessive Parkinson's disease (PD). Parkin translocates from the cytosol to depolarized mitochondria, ubiquitinates outer mitochondrial membrane proteins and induces selective autophagy of the damaged mitochondria (mitophagy). Here, we show that ubiquitin-specific protease 15 (USP15), a deubiquitinating enzyme (DUB) widely expressed in brain and other organs, opposes Parkin-mediated mitophagy, while a panel of other DUBs and a catalytically inactive version of USP15 do not. Moreover, knockdown of USP15 rescues the mitophagy defect of PD patient fibroblasts with PARK2 mutations and decreased Parkin levels. USP15 does not affect the ubiquitination status of Parkin or Parkin translocation to mitochondria, but counteracts Parkinmediated mitochondria! ubiquitination. Knockdown of the DUB CG8334, the closest homolog of USP15 in Drosophila, largely rescues the mitochondrial and behavioral defects of parkin RNAi flies. These data identify USP15 as an antagonist of Parkin and suggest that USP15 inhibition could be a therapeutic strategy for PD cases caused by reduced Parkin levels.