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.
Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
Jin-Rui
JR
Liang
Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK CIC Biogune Bizkaia Teknologi Parkea, Derio, Spain IKERBASQUE Basque Foundation for Science, Bilbao, Spain.
Aitor
A
Martinez
School of Biochemistry, University of Bristol, Bristol, UK.
Jon D
JD
Lane
CIC Biogune Bizkaia Teknologi Parkea, Derio, Spain IKERBASQUE Basque Foundation for Science, Bilbao, Spain.
Ugo
U
Mayor
Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK clague@liv.ac.uk urbe@liv.ac.uk.
Michael J
MJ
Clague
Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK clague@liv.ac.uk urbe@liv.ac.uk.
Sylvie
S
Urbé
D017209:Apoptosis / Q000235:genetics; D032701:Biomimetics; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002460:Cell Line; D004351:Drug Resistance; D015870:Gene Expression; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D063306:Mitophagy / Q000187:drug effects / Q000235:genetics; D010446:Peptide Fragments / Q000494:pharmacology; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D013869:Thiolester Hydrolases / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099202:PTEN-Induced Putative Kinase
D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; D061988:Proteasome Inhibitors; D011494:Protein Kinases; D011518:Proto-Oncogene Proteins; D013869:Thiolester Hydrolases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C474007:Bax protein (53-86); C532819:Usp30 protein, human; C111567:parkin protein
Parkin; TOM20; USP30; apoptosis; mitophagy