Rusilowicz-Jones, Emma V, Barone, Francesco G, Lopes, Fernanda Martins, Stephen, Elezabeth, Mortiboys, Heather, Urbe, Sylvie 
ORCID: 0000-0003-4735-9814 and Clague, Michael J ORCID: 0000-0003-3355-9479
(2022)
Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy.
LIFE SCIENCE ALLIANCE, 5 (2).
e202101287-.
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Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy.pdf - Published version Download (2MB) | Preview |
Abstract
The deubiquitylase USP30 is an actionable target considered for treatment of conditions associated with defects in the PINK1-PRKN pathway leading to mitophagy. We provide a detailed cell biological characterization of a benzosulphonamide 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 after mitochondrial depolarization. This includes enhancement of TOMM20 and SYNJ2BP ubiquitylation and phosphoubiquitin accumulation, alongside increased mitophagy. In dopaminergic neurons, generated from Parkinson disease patients carrying loss of function PRKN 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 U2OS 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Humans, Thiolester Hydrolases, Mitochondrial Proteins, Protease Inhibitors, Substrate Specificity, Dose-Response Relationship, Drug, Ubiquitination, Mitophagy |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 26 Jan 2022 14:25 |
| Last Modified: | 18 Jan 2023 21:14 |
| DOI: | 10.26508/lsa.202101287 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3147636 |
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