The deubiquitinase USP15 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 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.
Laboratory for Parkinson Research, Department of Neurosciences.
Tom
T
Cornelissen
Department of Human Genetics, KU Leuven, Leuven 3000, Belgium Center for the Biology of Disease, VIB, Leuven 3000, Belgium.
Dominik
D
Haddad
Laboratory for Parkinson Research, Department of Neurosciences.
Fieke
F
Wauters
Laboratory for Parkinson Research, Department of Neurosciences.
Cindy
C
Van Humbeeck
Department of Human Genetics, KU Leuven, Leuven 3000, Belgium Center for the Biology of Disease, VIB, Leuven 3000, Belgium.
Wim
W
Mandemakers
Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonards, New South Wales 2065, Australia.
Brianada
B
Koentjoro
Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, St Leonards, New South Wales 2065, Australia.
Carolyn
C
Sue
Department of Biochemistry, Ghent University, Ghent 9000, Belgium Department of Medical Protein Research, VIB, Ghent 9000, Belgium.
Kris
K
Gevaert
Department of Human Genetics, KU Leuven, Leuven 3000, Belgium Center for the Biology of Disease, VIB, Leuven 3000, Belgium.
Bart
B
De Strooper
Department of Human Genetics, KU Leuven, Leuven 3000, Belgium Center for the Biology of Disease, VIB, Leuven 3000, Belgium.
Patrik
P
Verstreken
Laboratory for Parkinson Research, Department of Neurosciences Department of Neurology, University Hospitals Leuven, Leuven 3000, Belgium wim.vandenberghe@uzleuven.be.
Wim
W
Vandenberghe
D000818:Animals; D002460:Cell Line; D004330:Drosophila; D004789:Enzyme Activation; D004843:Epistasis, Genetic; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy / Q000235:genetics; D008954:Models, Biological; D009154:Mutation; D009928:Organ Specificity / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C579226:USP15 protein, human; D064570:Ubiquitin-Specific Proteases