Novel highly selective inhibitors of ubiquitin specific protease 30 (USP30) accelerate mitophagy

Kluge, Arthur F.; Lagu, Bharat; Maiti, Pranab; Jaleel, Mahaboobi; Webb, M.; Malhotra, Jyoti; Mallat, Ashley; Srinivas, P. Akhila; Thompson, James E.

doi:10.1016/j.bmcl.2018.05.013

Cited by 92 publications

(65 citation statements)

References 20 publications

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“…The present study demonstrated a positive correlation in the co-expression of MIR600HG and ubiquitin-specific protease 30 (USP30). Furthermore, USP30 potentially reverses depolarization-induced PTEN induced kinase 1-parkin RBR E3 ubiquitin protein ligase-dependent mitophagy and has rapidly emerged as a potential therapeutic target in Parkinson's disease (36).…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of an autophagy‑related long non‑coding RNA signature in patients with oral and oropharyngeal squamous cell carcinoma

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of an autophagy‑related long non‑coding RNA signature in patients with oral and oropharyngeal squamous cell carcinoma

et al. 2020

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“…Some N-cyano pyrrolidines, which resemble known cathepsin C covalent inhibitors, have been reported in the patent literature to be dual inhibitors of UCHL1 and USP30 (Laine et al, 2011). High-throughput screening has also identified a racemic phenylalanine derivative as a USP30 inhibitor (Kluge et al, 2018). However, the specificity and biological activity of this compound has so far been only characterised superficially.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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“…Some Ncyano pyrrolidines, which resemble known cathepsin C covalent inhibitors, have been reported in the patent literature to be dual inhibitors of UCHL1 and USP30 (36). Highthroughput screening has also identified a racemic phenylalanine derivative as a USP30 inhibitor (37). However the specificity and biological activity of this compound has so far been only characterised superficially.…”

Section: Introductionmentioning

confidence: 99%

A novel USP30 inhibitor recapitulates genetic loss of USP30 and sets the trigger for PINK1-PARKIN amplification of mitochondrial ubiquitylation

Rusilowicz‐Jones

Jardine

Pinto-Fernández

et al. 2020

Preprint

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The mitochondrial deubiquitylase USP30 negatively regulates the selective autophagy of damaged mitochondria. It has been proposed as an actionable target to alleviate the loss of function of the mitophagy pathway governed by the Parkinson's Disease associated genes PINK1 and PRKN. We present the characterisation of a N-cyano pyrrolidine derived compound, FT3967385, with high selectivity for USP30. The compound is well tolerated with no loss of total mitochondrial mass. We demonstrate that ubiquitylation of TOM20, a component of the outer mitochondrial membrane import machinery that directly interacts with USP30, represents a robust biomarker for both USP30 loss and inhibition. We have conducted proteomics analyses on a SHSY5Y neuroblastoma cell line model to directly compare the effects of genetic loss of USP30 with selective inhibition in an unbiased fashion. 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 most 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. In this model, 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 and to a greater extent in cells either lacking USP30 or subject to USP30 inhibition.

show abstract

Novel highly selective inhibitors of ubiquitin specific protease 30 (USP30) accelerate mitophagy

Cited by 92 publications

References 20 publications

Prognostic significance of an autophagy‑related long non‑coding RNA signature in patients with oral and oropharyngeal squamous cell carcinoma

Prognostic significance of an autophagy‑related long non‑coding RNA signature in patients with oral and oropharyngeal squamous cell carcinoma

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

A novel USP30 inhibitor recapitulates genetic loss of USP30 and sets the trigger for PINK1-PARKIN amplification of mitochondrial ubiquitylation

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