Cornelissen Tom, Haddad Dominik, Wauters Fieke, Van Humbeeck Cindy, Mandemakers Wim, Koentjoro Brianada, Sue Carolyn, Gevaert Kris, De Strooper Bart, Verstreken Patrik, Vandenberghe Wim
Laboratory for Parkinson Research, Department of Neurosciences.
Department of Human Genetics, KU Leuven, Leuven 3000, Belgium Center for the Biology of Disease, VIB, Leuven 3000, Belgium.
Hum Mol Genet. 2014 Oct 1;23(19):5227-42. doi: 10.1093/hmg/ddu244. Epub 2014 May 22.
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 Parkin-mediated mitochondrial 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.
编码E3泛素连接酶Parkin的基因PARK2功能缺失突变是隐性帕金森病（PD）最常见的病因。Parkin从细胞质转移至去极化的线粒体，使线粒体外膜蛋白泛素化，并诱导受损线粒体的选择性自噬（线粒体自噬）。在此，我们表明泛素特异性蛋白酶15（USP15）是一种在脑和其他器官中广泛表达的去泛素化酶（DUB），它会对抗Parkin介导的线粒体自噬，而其他一系列DUB以及USP15的催化失活版本则不会。此外，敲低USP15可挽救携带PARK2突变且Parkin水平降低的PD患者成纤维细胞的线粒体自噬缺陷。USP15不影响Parkin的泛素化状态或Parkin向线粒体的转位，但会抵消Parkin介导的线粒体泛素化。敲低果蝇中USP15最接近的同源物DUB CG8334，可在很大程度上挽救帕金森病RNA干扰果蝇的线粒体和行为缺陷。这些数据确定USP15是Parkin的拮抗剂，并表明抑制USP15可能是针对因Parkin水平降低导致的PD病例的一种治疗策略。
