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



Rusilowicz-Jones, Emma V, Jardine, Jane ORCID: 0000-0002-7646-9636, Kallinos, Andreas ORCID: 0000-0001-8771-963X, Pinto-Fernandez, Adan, Guenther, Franziska, Giurrandino, Mariacarmela, Barone, Francesco G, McCarron, Katy, Burke, Christopher J, Murad, Alejandro
et al (show 19 more authors) (2020) USP30 sets a trigger threshold for PINK1–PARKIN amplification of mitochondrial ubiquitylation. Life Science Alliance, 3 (8).

[img] Text
e202000768.full.pdf - OA Published Version

Download (3MB) | Preview

Abstract

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.

Item Type: Article
Uncontrolled Keywords: Chemical Biology, Cell Biology, Aging
Depositing User: Symplectic Admin
Date Deposited: 16 Sep 2020 08:31
Last Modified: 03 Mar 2021 09:12
DOI: 10.26508/lsa.202000768
Open Access URL: http://doi.org/10.26508/lsa.202000768
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3101392