JOURNAL ARTICLE

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

Thomas M Durcan, Matthew Y Tang, Joëlle R Pérusse, Eman A Dashti, Miguel A Aguileta, Gian-Luca McLelland, Priti Gros, Thomas A Shaler, Denis Faubert, Benoit Coulombe, Edward A Fon
EMBO Journal 2014 November 3, 33 (21): 2473-91
25216678
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.

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