Abstract
Mitochondria play a pivotal role in the orchestration of cell death pathways. Here, we show that the control of ubiquitin dynamics at mitochondria contributes to the regulation of apoptotic cell death. The unique mitochondrial deubiquitylase, USP30, opposes Parkin-dependent ubiquitylation of TOM20, and its depletion enhances depolarization-induced cell death in Parkin-overexpressing cells. Importantly, USP30 also regulates BAX/BAK-dependent apoptosis, and its depletion sensitizes cancer cells to BH3-mimetics. These results provide the first evidence for a fundamental role of USP30 in determining the threshold for mitochondrial cell death and suggest USP30 as a potential target for combinatorial anti-cancer therapy.
Keywords:
Parkin; TOM20; USP30; apoptosis; mitophagy.
© 2015 The Authors. Published under the terms of the CC BY 4.0 license.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis* / genetics
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Biomimetics
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Carbonyl Cyanide m-Chlorophenyl Hydrazone / pharmacology
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Cell Line
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Drug Resistance
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Gene Expression
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Humans
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Mitochondria / drug effects
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Mitochondria / genetics
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Mitochondria / metabolism*
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Mitochondrial Proteins / metabolism*
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Mitophagy / drug effects
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Mitophagy / genetics
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Peptide Fragments / pharmacology
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Proteasome Inhibitors / pharmacology
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Protein Binding
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Proto-Oncogene Proteins / pharmacology
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Thiolester Hydrolases / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination*
Substances
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Bax protein (53-86)
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Mitochondrial Proteins
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Peptide Fragments
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Proteasome Inhibitors
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Proto-Oncogene Proteins
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Usp30 protein, human
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Carbonyl Cyanide m-Chlorophenyl Hydrazone
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Ubiquitin-Protein Ligases
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parkin protein
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Protein Kinases
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PTEN-induced putative kinase
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Thiolester Hydrolases