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Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy

Emma V. Rusilowicz-Jones, View ORCID ProfileFrancesco G. Barone, Fernanda Martins Lopes, Elizabeth Stephen, View ORCID ProfileHeather Mortiboys, View ORCID ProfileSylvie Urbé, View ORCID ProfileMichael J. Clague
doi: https://doi.org/10.1101/2021.04.28.441730
Emma V. Rusilowicz-Jones
1Dept. of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 3BX, UK
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Francesco G. Barone
1Dept. of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 3BX, UK
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Fernanda Martins Lopes
2Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK
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Elizabeth Stephen
2Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK
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Heather Mortiboys
2Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, 385a Glossop Road, Sheffield, S10 2HQ, UK
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Sylvie Urbé
1Dept. of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 3BX, UK
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  • For correspondence: urbe@liv.ac.uk clague@liv.ac.uk
Michael J. Clague
1Dept. of Molecular Physiology and Cell Signaling, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 3BX, UK
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  • For correspondence: urbe@liv.ac.uk clague@liv.ac.uk
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Abstract

The deubiquitylase USP30 is an actionable target considered for treatment of conditions associated with defects in the PINK1/Parkin pathway leading to mitophagy. These include Parkinson’s disease and pulmonary fibrosis. We provide a detailed cell biological characterisation of a benzenesulphonamide molecule, compound 39, that has previously been reported to inhibit USP30 in an in vitro enzymatic assay. The current compound offers increased selectivity over previously described inhibitors. It enhances mitophagy and generates a signature response for USP30 inhibition following mitochondrial depolarisation. This includes enhancement of TOM20 and SYNJ2BP ubiquitylation and phosphoubiquitin accumulation, alongside increased mitophagy. In dopaminergic neurons, generated from Parkinson’s disease patients carrying loss of function Parkin mutations, compound 39 could significantly restore mitophagy to a level approaching control values. USP30 is located on both mitochondria and peroxisomes and has also been linked to the PINK1 independent pexophagy pathway. Using a fluorescence reporter of pexophagy expressed in U20S cells, we observe increased pexophagy upon application of compound 39 that recapitulates the previously described effect for USP30 depletion. This provides the first pharmacological intervention with a synthetic molecule to enhance peroxisome turnover.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted April 28, 2021.
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Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy
Emma V. Rusilowicz-Jones, Francesco G. Barone, Fernanda Martins Lopes, Elizabeth Stephen, Heather Mortiboys, Sylvie Urbé, Michael J. Clague
bioRxiv 2021.04.28.441730; doi: https://doi.org/10.1101/2021.04.28.441730
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Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy
Emma V. Rusilowicz-Jones, Francesco G. Barone, Fernanda Martins Lopes, Elizabeth Stephen, Heather Mortiboys, Sylvie Urbé, Michael J. Clague
bioRxiv 2021.04.28.441730; doi: https://doi.org/10.1101/2021.04.28.441730

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