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Nat Cell Biol. 2015 Feb;17(2):160-9. doi: 10.1038/ncb3097. Epub 2015 Jan 26.

USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria.

Author information

1
Department of Early Discovery Biochemistry, Genentech, Inc., 1 DNA Way South San Francisco, California 94080, USA.
2
Department of Protein Chemistry, Genentech, Inc., 1 DNA Way South San Francisco, California 94080, USA.
3
Department of Neuroscience, Genentech, Inc., 1 DNA Way South San Francisco, California 94080, USA.
4
Department of Structural Biology, Genentech, Inc., 1 DNA Way South San Francisco, California 94080, USA.

Abstract

Multiple lines of evidence indicate that mitochondrial dysfunction is central to Parkinson's disease. Here we investigate the mechanism by which parkin, an E3 ubiquitin ligase, and USP30, a mitochondrion-localized deubiquitylase, regulate mitophagy. We find that mitochondrial damage stimulates parkin to assemble Lys 6, Lys 11 and Lys 63 chains on mitochondria, and that USP30 is a ubiquitin-specific deubiquitylase with a strong preference for cleaving Lys 6- and Lys 11-linked multimers. Using mass spectrometry, we show that recombinant USP30 preferentially removes these linkage types from intact ubiquitylated mitochondria and counteracts parkin-mediated ubiquitin chain formation in cells. These results, combined with a series of chimaera and localization studies, afford insights into the mechanism by which a balance of ubiquitylation and deubiquitylation regulates mitochondrial homeostasis, and suggest a general mechanism for organelle autophagy.

PMID:
25621951
DOI:
10.1038/ncb3097
[Indexed for MEDLINE]

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