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Lookup NU author(s): Dr Akshada Gajbhiye,
Professor Matthias TrostORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2020 Rusilowicz-Jones et al.The mitochondrial deubiquitylase USP30 negatively regulates the selective autophagy of damaged mitochondria. We present the characterisation of an N-cyano pyrrolidine compound, FT3967385, with high selectivity for USP30. We demonstrate that ubiquitylation of TOM20, a component of the outer mitochondrial membrane import machinery, represents a robust biomarker for both USP30 loss and inhibition. A proteomics analysis, on a SHSY5Y neuroblastoma cell line model, directly compares the effects of genetic loss of USP30 with chemical inhibition. We have thereby identified a subset of ubiquitylation events consequent to mitochondrial depolarisation that are USP30 sensitive. Within responsive elements of the ubiquitylome, several components of the outer mitochondrial membrane transport (TOM) complex are prominent. Thus, our data support a model whereby USP30 can regulate the availability of ubiquitin at the specific site of mitochondrial PINK1 accumulation following membrane depolarisation. USP30 deubiquitylation of TOM complex components dampens the trigger for the Parkin-dependent amplification of mitochondrial ubiquitylation leading to mitophagy. Accordingly, PINK1 generation of phospho-Ser65 ubiquitin proceeds more rapidly in cells either lacking USP30 or subject to USP30 inhibition.
Author(s): Rusilowicz-Jones EV, Jardine J, Kallinos A, Pinto-Fernandez A, Guenther F, Giurrandino M, Barone FG, McCarron K, Burke CJ, Murad A, Martinez A, Marcassa E, Gersch M, Buckmelter AJ, Kayser-Bricker KJ, Lamoliatte F, Gajbhiye A, Davis S, Scott HC, Murphy E, England K, Mortiboys H, Komander D, Trost M, Kessler BM, Ioannidis S, Ahlijanian MK, Urbe S, Clague MJ
Publication type: Article
Publication status: Published
Journal: Life Science Alliance
Online publication date: 07/07/2020
Acceptance date: 26/06/2020
Date deposited: 21/07/2020
ISSN (electronic): 2575-1077
Publisher: Life Science Alliance LLC
PubMed id: 32636217
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