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PLoS Genet. 2014 Dec 4;10(12):e1004861. doi: 10.1371/journal.pgen.1004861. eCollection 2014 Dec.

Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering.

Author information

1
Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
2
Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan.
3
Department of Neuroscience for Neurodegenerative Disorders, Juntendo University Graduate School of Medicine, Tokyo, Japan.
4
Department of Molecular and Cellular BioAnalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
5
Department of Life Science, University of Seoul, Seoul, Korea.
6
Department of Neurology, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Research for Parkinson's Disease, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Abstract

The kinase PINK1 and the E3 ubiquitin (Ub) ligase Parkin participate in mitochondrial quality control. The phosphorylation of Ser65 in Parkin's ubiquitin-like (UBl) domain by PINK1 stimulates Parkin activation and translocation to damaged mitochondria, which induces mitophagy generating polyUb chain. However, Parkin Ser65 phosphorylation is insufficient for Parkin mitochondrial translocation. Here we report that Ser65 in polyUb chain is also phosphorylated by PINK1, and that phosphorylated polyUb chain on mitochondria tethers Parkin at mitochondria. The expression of Tom70MTS-4xUb SE, which mimics phospho-Ser65 polyUb chains on the mitochondria, activated Parkin E3 activity and its mitochondrial translocation. An E3-dead form of Parkin translocated to mitochondria with reduced membrane potential in the presence of Tom70(MTS)-4xUb SE, whereas non-phospho-polyUb mutant Tom70(MTS)-4xUb SA abrogated Parkin translocation. Parkin binds to the phospho-polyUb chain through its RING1-In-Between-RING (IBR) domains, but its RING0-linker is also required for mitochondrial translocation. Moreover, the expression of Tom70(MTS)-4xUb SE improved mitochondrial degeneration in PINK1-deficient, but not Parkin-deficient, Drosophila. Our study suggests that the phosphorylation of mitochondrial polyUb by PINK1 is implicated in both Parkin activation and mitochondrial translocation, predicting a chain reaction mechanism of mitochondrial phospho-polyUb production by which rapid translocation of Parkin is achieved.

PMID:
25474007
PMCID:
PMC4256268
DOI:
10.1371/journal.pgen.1004861
[Indexed for MEDLINE]
Free PMC Article

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