The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy
2014
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.
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