期刊
MOLECULAR CELL
卷 70, 期 2, 页码 211-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2018.03.012
关键词
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资金
- NIH [R37 NS083524, RO1 GM095567, RO1 GM067945, K01DK098285]
- Michael J. Fox Foundation [11115.01]
- Edward R. and Anne G. Lefler Center Postdoctoral Fellowship
- Sara Elizabeth O'Brien Trust Postdoctoral Fellowship
- Cancer Research Society/BMO Bank of Montreal Scholarship for the Next Generation of Scientists
- Genome Canada Disruptive Innovation in Genomics [OGI-119]
- Harvard Medical School Cell Biology Initiative for Molecular Trafficking and Neurodegeneration
Flux through kinase and ubiquitin-driven signaling systems depends on the modification kinetics, stoichiometry, primary site specificity, and target abundance within the pathway, yet we rarely understand these parameters and their spatial organization within cells. Here we develop temporal digital snapshots of ubiquitin signaling on the mitochondrial outermembrane in embryonic stem cell-derived neurons, and we model HeLa cell systems upon activation of the PINK1 kinase and PARKIN ubiquitin ligase by proteomic counting of ubiquitylation and phosphorylation events. We define the kinetics and site specificity of PARKIN-dependent target ubiquitylation, and we demonstrate the power of this approach to quantify pathway modulators and to mechanistically define the role of PARKIN UBL phosphorylation in pathway activation in induced neurons. Finally, through modulation of pS65-Ub on mitochondria, we demonstrate that Ub hyper-phosphorylation is inhibitory to mitophagy receptor recruitment, indicating that pS65-Ub stoichiometry in vivo is optimized to coordinate PARKIN recruitment via pS65-Ub and mitophagy receptors via unphosphorylated chains.
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