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

被引：84

作者：

Rusilowicz-Jones, Emma, V ^{[1
]}

Jardine, Jane ^{[1
]}

Kallinos, Andreas ^{[1
]}

Pinto-Fernandez, Adan ^{[2
]}

Guenther, Franziska ^{[3
]}

Giurrandino, Mariacarmela ^{[3
]}

Barone, Francesco G. ^{[1
]}

McCarron, Katy ^{[1
]}

Burke, Christopher J. ^{[4
,11
]}

Murad, Alejandro ^{[4
,12
]}

Martinez, Aitor ^{[1
]}

Marcassa, Elena ^{[1
]}

Gersch, Malte ^{[5
,6
]}

Buckmelter, Alexandre J. ^{[4
,14
]}

Kayser-Bricker, Katherine J. ^{[4
,13
]}

Lamoliatte, Frederic ^{[10
]}

Gajbhiye, Akshada ^{[10
]}

Davis, Simon ^{[2
]}

Scott, Hannah C. ^{[2
]}

Murphy, Emma ^{[3
]}

England, Katherine ^{[3
]}

Mortiboys, Heather ^{[7
]}

Komander, David ^{[8
,9
]}

Trost, Matthias ^{[10
]}

Kessler, Benedikt M. ^{[2
]}

Ioannidis, Stephanos ^{[4
,15
]}

Ahlijanian, Michael K. ^{[4
,16
]}

Urbe, Sylvie ^{[1
]}

Clague, Michael J. ^{[1
]}

机构：

[1] Univ Liverpool, Inst Translat Med, Dept Cellular & Mol Physiol, Liverpool, Merseyside, England

[2] Univ Oxford, Target Discovery Inst, Nuffield Dept Med, Oxford, England

[3] Univ Oxford, Alzheimers Res UK Oxford Drug Discovery Inst, Target Discovery Inst, Nuffield Dept Med, Oxford, England

[4] FORMA Therapeut, Watertown, MA USA

[5] Max Planck Inst Mol Physiol, Chem Genom Ctr, Dortmund, Germany

[6] Tech Univ Dortmund, Dept Chem & Chem Biol, Dortmund, Germany

[7] Univ Sheffield, Sheffield Inst Translat Neurosci SITraN, Sheffield, S Yorkshire, England

[8] Walter & Eliza Hall Inst Med Res, Ubiquitin Signalling Div, Parkville, Vic, Australia

[9] Univ Melbourne, Dept Med Biol, Melbourne, Vic, Australia

[10] Univ Newcastle, Fac Med Sci, Biosci Inst, Lab Biol Mass Spectrometry, Newcastle, NSW, Australia

[11] Yuman Therapeut Discovery Biol, Cambridge, MA USA

[12] Skyhawk Therapeut, Neurobiol, Waltham, MA USA

[13] Halda Therapeut, Branford, CT USA

[14] Morphic Therapeut, Waltham, MA USA

[15] H3 Biomed, Cambridge, MA USA

[16] Pinteon Therapeut, Newton, MA USA

来源：

LIFE SCIENCE ALLIANCE | 2020年 / 3卷 / 08期

基金：

英国医学研究理事会; 英国惠康基金;

关键词：

UBIQUITIN CHAINS; OUTER-MEMBRANE; PARKIN; PINK1; SPECIFICITY; MECHANISM; MITOPHAGY; PHOSPHORYLATION; LOCALIZATION; RECRUITMENT;

D O I：

10.26508/lsa.202000768

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

共 68 条

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