RT Journal Article
SR Electronic
T1 USP30 sets a trigger threshold for PINK1–PARKIN amplification of mitochondrial ubiquitylation
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000768
DO 10.26508/lsa.202000768
VO 3
IS 8
A1 Emma V Rusilowicz-Jones
A1 Jane Jardine
A1 Andreas Kallinos
A1 Adan Pinto-Fernandez
A1 Franziska Guenther
A1 Mariacarmela Giurrandino
A1 Francesco G Barone
A1 Katy McCarron
A1 Christopher J Burke
A1 Alejandro Murad
A1 Aitor Martinez
A1 Elena Marcassa
A1 Malte Gersch
A1 Alexandre J Buckmelter
A1 Katherine J Kayser-Bricker
A1 Frederic Lamoliatte
A1 Akshada Gajbhiye
A1 Simon Davis
A1 Hannah C Scott
A1 Emma Murphy
A1 Katherine England
A1 Heather Mortiboys
A1 David Komander
A1 Matthias Trost
A1 Benedikt M Kessler
A1 Stephanos Ioannidis
A1 Michael K Ahlijanian
A1 Sylvie Urbé
A1 Michael J Clague
YR 2020
UL https://www.life-science-alliance.org/content/3/8/e202000768.abstract
AB 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.