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PMID:24852371

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Citation

Cornelissen, T, Haddad, D, Wauters, F, Van Humbeeck, C, Mandemakers, W, Koentjoro, B, Sue, C, Gevaert, K, De Strooper, B, Verstreken, P and Vandenberghe, W (2014) The deubiquitinase USP15 antagonizes Parkin-mediated mitochondrial ubiquitination and mitophagy. Hum. Mol. Genet. 23:5227-42

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). 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.

Links

PubMed Online version:10.1093/hmg/ddu244

Keywords

Animals; Cell Line; Drosophila; Enzyme Activation; Epistasis, Genetic; Female; Fibroblasts/metabolism; Gene Expression; Gene Knockdown Techniques; Humans; Male; Mitochondria/genetics; Mitochondria/metabolism; Mitochondrial Degradation/genetics; Models, Biological; Mutation; Organ Specificity/genetics; Parkinson Disease/genetics; Parkinson Disease/metabolism; Protein Binding; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Ubiquitin-Specific Proteases/genetics; Ubiquitin-Specific Proteases/metabolism; Ubiquitination/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DROME:PRKN

involved_in

GO:0008344: adult locomotory behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:PRKN

involved_in

GO:0007005: mitochondrion organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q7KTX7

involved_in

GO:0007005: mitochondrion organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

DROME:Q7KTX7

involved_in

GO:0008344: adult locomotory behavior

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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