USP30 deubiquitylates mitochondrial Parkin substrates and restricts apoptotic cell death.
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.
Mesh Terms:
Apoptosis, Biomimetics, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Cell Line, Drug Resistance, Gene Expression, Humans, Mitochondria, Mitochondrial Degradation, Mitochondrial Proteins, Peptide Fragments, Proteasome Inhibitors, Protein Binding, Protein Kinases, Proto-Oncogene Proteins, Thiolester Hydrolases, Ubiquitin-Protein Ligases, Ubiquitination
Apoptosis, Biomimetics, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Cell Line, Drug Resistance, Gene Expression, Humans, Mitochondria, Mitochondrial Degradation, Mitochondrial Proteins, Peptide Fragments, Proteasome Inhibitors, Protein Binding, Protein Kinases, Proto-Oncogene Proteins, Thiolester Hydrolases, Ubiquitin-Protein Ligases, Ubiquitination
EMBO Rep.
Date: May. 01, 2015
PubMed ID: 25739811
View in: Pubmed Google Scholar
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