Identification of a deubiquitinase that antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy

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 mitochondrial substrates and induces autophagic mitochondrial clearance (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 other DUBs or a catalytically inactive version of USP15 do not. Moreover, knockdown of USP15 rescues the mitophagy defect of PARK2 mutant PD patient fibroblasts. 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 behavioural 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. Supported by Research Foundation Flanders (FWO), KU Leuven, ERC, BELSPO and VIB.status: publishe