title: USP8 and PARK2/parkin-mediated mitophagy.
abstract: The Parkinson disease (PD)-associated E3-ubiquitin (Ub) ligase PARK2/parkin plays a central role in many stress response pathways, and in particular, in mitochondrial quality control. Within this pathway, PARK2 activation is accompanied by a robust increase in its autoubiquitination, followed by clearance of the damaged mitochondria by selective autophagy (mitophagy). Yet, little is known about how this auto-ubiquitination is regulated during mitophagy. In our study, we demonstrate that PARK2 forms predominantly K6-linked Ub conjugates on itself. Moreover, PARK2 interacts with the deubiquitinating enzyme USP8 that preferentially removes these K6-linked conjugates, thereby regulating the activity and function of PARK2 in the pathway. When USP8 is silenced, a persistence of K6-linked Ub conjugates on PARK2 delays both its translocation to damaged mitochondria and successful completion of mitophagy. Taken together, these findings implicate a novel role for K6-linked Ub conjugates and USP8-mediated deubiquitination in the regulation of PARK2 in mitochondrial quality control.
authors.affiliation: a McGill Parkinson's Program ; Department of Neurology and Neurosurgery ; Montreal Neurological Institute ; McGill University ; Montreal , Canada.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Durcan
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fon
mesh_terms: D001343:Autophagy / Q000502:physiology*; D010450:Endopeptidases / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / 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: K6 Ub-linkages; PARK2/Parkin; USP8; deubiquitination; mitophagy