USP30 deubiquitylates mitochondrial Parkin substrates and restricts apoptotic cell death |
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| Authors: | Jin-Rui Liang Aitor Martinez Jon D Lane Ugo Mayor Michael J Clague Sylvie Urbé |
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| Affiliation: | 1Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK;2CIC Biogune, Bizkaia Teknologi Parkea, Derio, Spain;3IKERBASQUE, Basque Foundation for Science, Bilbao, Spain;4School of Biochemistry, University of Bristol, Bristol, UK |
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| 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. |
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| Keywords: | apoptosis mitophagy Parkin TOM20 USP30 |
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