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EMBO J. 2014 Nov 3;33(21):2473-91. doi: 10.15252/embj.201489729. Epub 2014 Sep 12.

USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin.

Author information

1
McGill Parkinson Program, Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
2
Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC, Canada.
3
Physics Laboratory, SRI International, Menlo Park, CA, USA.
4
Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC, Canada Department of Biochemistry, Université de Montréal, Montréal, QC, Canada.
5
McGill Parkinson Program, Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC, Canada ted.fon@mcgill.ca.

Abstract

Mutations in the Park2 gene, encoding the E3 ubiquitin-ligase parkin, are responsible for a familial form of Parkinson's disease (PD). Parkin-mediated ubiquitination is critical for the efficient elimination of depolarized dysfunctional mitochondria by autophagy (mitophagy). As damaged mitochondria are a major source of toxic reactive oxygen species within the cell, this pathway is believed to be highly relevant to the pathogenesis of PD. Little is known about how parkin-mediated ubiquitination is regulated during mitophagy or about the nature of the ubiquitin conjugates involved. We report here that USP8/UBPY, a deubiquitinating enzyme not previously implicated in mitochondrial quality control, is critical for parkin-mediated mitophagy. USP8 preferentially removes non-canonical K6-linked ubiquitin chains from parkin, a process required for the efficient recruitment of parkin to depolarized mitochondria and for their subsequent elimination by mitophagy. This work uncovers a novel role for USP8-mediated deubiquitination of K6-linked ubiquitin conjugates from parkin in mitochondrial quality control.

KEYWORDS:

USP8; deubiquitination; mitophagy; parkin; ubiquitin

PMID:
25216678
PMCID:
PMC4283406
DOI:
10.15252/embj.201489729
[Indexed for MEDLINE]
Free PMC Article

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