USP30 and parkin homeostatically regulate atypical ubiquitin chains on mitochondria

作者：Cunningham Christian N; Baughman Joshua M; Phu Lilian; Tea Joy S; Yu Christine; Coons Mary; Kirkpatrick Donald S^*; Bingol Bans; Corn Jacob E

来源：Nature Cell Biology, 2015, 17(2): 160-+.

DOI：10.1038/ncb3097

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.

• 出版日期2015-2