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USP30 sets a trigger threshold for PINK1-PARKIN amplification of mitochondrial ubiquitylation

Lookup NU author(s): Dr Akshada Gajbhiye, Professor Matthias Trost

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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

Year: 2020

Volume: 3

Issue: 8

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

URL: https://doi.org/10.26508/lsa.202000768

DOI: 10.26508/lsa.202000768

PubMed id: 32636217


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