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

Collapse authors list.
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) , Martinez, Aitor, Marcassa, Elena, Gersch, Malte, Buckmelter, Alexandre J, Kayser-Bricker, Katherine J, Lamoliatte, Frederic, Gajbhiye, Akshada, Davis, Simon, Scott, Hannah C, Murphy, Emma, England, Katherine, Mortiboys, Heather, Komander, David, Trost, Matthias, Kessler, Benedikt M, Ioannidis, Stephanos, Ahlijanian, Michael K, Urbe, Sylvie ORCID: 0000-0003-4735-9814 and Clague, Michael J ORCID: 0000-0003-3355-9479 (2020) USP30 sets a trigger threshold for PINK1-PARKIN amplification of mitochondrial ubiquitylation. LIFE SCIENCE ALLIANCE, 3 (8). e202000768-.

Access the full-text of this item by clicking on the Open Access link.

Text LSA-2020-00768-TRR_Merged_PDF.pdf - Author Accepted Manuscript Download (16MB) | 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:	Hela Cells, Mitochondria, Humans, Thiolester Hydrolases, Ubiquitin-Protein Ligases, Protein Kinases, Membrane Transport Proteins, Receptors, Cell Surface, Mitochondrial Proteins, Ubiquitin, Mitochondrial Membranes, Ubiquitination, Neural Stem Cells, Mitophagy, Mitochondrial Precursor Protein Import Complex Proteins
Depositing User:	Symplectic Admin
Date Deposited:	14 Jul 2020 09:37
Last Modified:	18 Jan 2023 23:46
DOI:	10.26508/lsa.202000768
Open Access URL:	https://www.life-science-alliance.org/content/3/8/...
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3093573