The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy

Abstract 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). Parkintranslocates from the cytosol to depolarized mitochondria, ubiquitinates outer mitochondrial membraneproteins 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 mitophagydefect of PD patient fibroblasts with PARK2 mutations and decreased Parkinlevels. USP15 does not affect the ubiquitinationstatus of Parkinor Parkintranslocation 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 parkinRNAi flies. These data identify USP15 as an antagonist of Parkinand suggest that USP15 inhibition could be a therapeutic strategy for PD cases caused by reduced Parkinlevels.