USP30 deubiquitylates mitochondrial Parkin substrates and restricts apoptotic cell death

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. USP30, recently described to counteract Parkin E3 ligase activity on mitochondria, is shown to regulate the mitochondrial pathway of apoptotic cell death in response to Parkin overexpression and the broadly used BH3‐mimetic therapeutic compounds. USP30, recently described to counteract Parkin E3 ligase activity on mitochondria, is shown to regulate the mitochondrial pathway of apoptotic cell death in response to Parkin overexpression and the broadly used BH3‐mimetic therapeutic compounds.

Cited by papers we hold 10

• Mitophagy: Molecular Mechanisms, New Concepts on Parkin Activation and the Emerging Role of AMPK/ULK1 Axis · 2021
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• Molecular mechanisms and physiological functions of mitophagy · 2021
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• Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response · 2021
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• Global Landscape and Dynamics of Parkin and USP30-Dependent Ubiquitylomes in iNeurons during Mitophagic Signaling · 2020
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• USP30 sets a trigger threshold for PINK1–PARKIN amplification of mitochondrial ubiquitylation · 2020
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• The role of ubiquitin-specific peptidases in cancer progression · 2019
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• Dual role of USP30 in controlling basal pexophagy and mitophagy · 2018
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• Crosstalk between Autophagy and Apoptosis: Potential and Emerging Therapeutic Targets for Cardiac Diseases · 2016
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• Ubiquitin modifications · 2016
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• Mitophagy programs: mechanisms and physiological implications of mitochondrial targeting by autophagy · 2015
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