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 Rusilowicz-Jones, Emma V
A1 Jardine, Jane
A1 Kallinos, Andreas
A1 Pinto-Fernandez, Adan
A1 Guenther, Franziska
A1 Giurrandino, Mariacarmela
A1 Barone, Francesco G
A1 McCarron, Katy
A1 Burke, Christopher J
A1 Murad, Alejandro
A1 Martinez, Aitor
A1 Marcassa, Elena
A1 Gersch, Malte
A1 Buckmelter, Alexandre J
A1 Kayser-Bricker, Katherine J
A1 Lamoliatte, Frederic
A1 Gajbhiye, Akshada
A1 Davis, Simon
A1 Scott, Hannah C
A1 Murphy, Emma
A1 England, Katherine
A1 Mortiboys, Heather
A1 Komander, David
A1 Trost, Matthias
A1 Kessler, Benedikt M
A1 Ioannidis, Stephanos
A1 Ahlijanian, Michael K
A1 Urbé, Sylvie
A1 Clague, Michael J
YR 2020
UL http://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.