title: USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin.
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.
authors.affiliation: McGill Parkinson Program, Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Durcan
authors.affiliation: McGill Parkinson Program, Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
authors.forename: Matthew Y
authors.initials: MY
authors.lastname: Tang
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC, Canada.
authors.forename: Joëlle R
authors.initials: JR
authors.lastname: Pérusse
authors.affiliation: McGill Parkinson Program, Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
authors.forename: Eman A
authors.initials: EA
authors.lastname: Dashti
authors.affiliation: McGill Parkinson Program, Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Aguileta
authors.affiliation: McGill Parkinson Program, Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
authors.forename: Gian-Luca
authors.initials: GL
authors.lastname: McLelland
authors.affiliation: McGill Parkinson Program, Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
authors.forename: Priti
authors.initials: P
authors.lastname: Gros
authors.affiliation: Physics Laboratory, SRI International, Menlo Park, CA, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Shaler
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Faubert
authors.affiliation: Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC, Canada Department of Biochemistry, Université de Montréal, Montréal, QC, Canada.
authors.forename: Benoit
authors.initials: B
authors.lastname: Coulombe
authors.affiliation: McGill Parkinson Program, Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, QC, Canada ted.fon@mcgill.ca.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fon
mesh_terms: D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy / Q000502:physiology*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D010450:Endopeptidases; C541534:USP8 protein, human; D043222:Ubiquitin Thiolesterase
keywords: USP8; deubiquitination; mitophagy; parkin; ubiquitin