The deubiquitinase USP15 antagonizes Parkin-mediated mitophagy

Mutations in the gene for the E3 ubiquitin ligase Parkin are the most common cause of recessive Parkinson’s disease (PD). Recently, Parkin has been shown in various cell models to translocate from the cytosol to depolarized mitochondria. After translocation, Parkin ubiquitinates mitochondrial outer membrane proteins and triggers autophagic removal of these mitochondria (mitophagy) (1). In addition to E3 ubiquitin ligases, the human proteome contains approximately 80 deubiquinating enzymes (DUBs), which remove ubiquitin from substrates. Whether any DUB specifically reverses the enzymatic effects of Parkin, is currently unknown. In a previous TAP/MS study (2), we identified the DUB Ubiquitin-specific protease 15 (USP15) as a Parkin interactor. Here, we show that USP15 opposes the mitochondrial effects of Parkin.status: publishe