Proteasome Activation by Small Molecules

Yves Leestemaker; Annemieke de Jong; Katharina F Witting; Renske Penning; Karianne Schuurman; Boris Rodenko; Esther A Zaal; Bert van de Kooij; Stefan Laufer; Albert J R Heck; Jannie Borst; Wiep Scheper; Celia R Berkers; Huib Ovaa

doi:10.1016/j.chembiol.2017.05.010

Proteasome Activation by Small Molecules

Yves Leestemaker, Annemieke de Jong, Katharina F Witting, Renske Penning, Karianne Schuurman, Boris Rodenko, Esther A Zaal, Bert van de Kooij, Stefan Laufer, Albert J R Heck, Jannie Borst, Wiep Scheper, Celia R Berkers, Huib Ovaa

Functional Genomics

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Drugs that increase 26S proteasome activity have potential therapeutic applications in the treatment of neurodegenerative diseases. A chemical genetics screen of over 2,750 compounds using a proteasome activity probe as a readout in a high-throughput live-cell fluorescence-activated cell sorting-based assay revealed more than ten compounds that increase proteasome activity, with the p38 MAPK inhibitor PD169316 being one of the most potent ones. Genetic and chemical inhibition of either p38 MAPK, its upstream regulators, ASK1 and MKK6, and downstream target, MK2, enhance proteasome activity. Chemical activation of the 26S proteasome increases PROTAC-mediated and ubiquitin-dependent protein degradation and decreases the levels of both overexpressed and endogenous α-synuclein, without affecting the overall protein turnover. In addition, survival of cells overexpressing toxic α-synuclein assemblies is increased in the presence of p38 MAPK inhibitors. These findings highlight the potential of activation of 26S proteasome activity and that this can be achieved through multiple mechanisms by distinct molecules.

Original language	English
Pages (from-to)	725-736.e7
Journal	Cell Chemical Biology
Volume	24
Issue number	6
DOIs	https://doi.org/10.1016/j.chembiol.2017.05.010
Publication status	Published - 22 Jun 2017

Funding

The authors would like to thank Rob Zwart for technical assistance, Lan Huang for reagents, Koraljka Husnjak for critical reading of the manuscript, Olivier Coux for practical advice, and David Sullivan, Jun Liu, and Curtis Chong for providing us with the Johns Hopkins Clinical Compound Library (JHCCL) version 1.0. This work was supported by a VICI grant to H.O. from the Netherlands Organisation for Scientific Research (NWO) (project 724.013.002). C.R.B. was financially supported by a VENI grant (project 722.013.009) from NWO. R.P. and A.J.R.H. acknowledge NWO-supported large scale proteomics facility Proteins@Work (project 184.032.201) embedded in the Netherlands Proteomic Center. The authors would like to thank Rob Zwart for technical assistance, Lan Huang for reagents, Koraljka Husnjak for critical reading of the manuscript, Olivier Coux for practical advice, and David Sullivan, Jun Liu, and Curtis Chong for providing us with the Johns Hopkins Clinical Compound Library (JHCCL) version 1.0. This work was supported by a VICI grant to H.O. from the Netherlands Organisation for Scientific Research (NWO) (project 724.013.002 ). C.R.B. was financially supported by a VENI grant (project 722.013.009 ) from NWO. R.P. and A.J.R.H. acknowledge NWO-supported large scale proteomics facility Proteins@Work (project 184.032.201 ) embedded in the Netherlands Proteomic Center.

Funders	Funder number
C.R.B.
NWO-supported	184.032.201
VENI	722.013.009
VICI
Johns Hopkins University
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	724.013.002

Keywords

Cell Line, Tumor
Enzyme Activation
Humans
Imidazoles
Journal Article
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Proteolysis
p38 Mitogen-Activated Protein Kinases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.chembiol.2017.05.010

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title = "Proteasome Activation by Small Molecules",

abstract = "Drugs that increase 26S proteasome activity have potential therapeutic applications in the treatment of neurodegenerative diseases. A chemical genetics screen of over 2,750 compounds using a proteasome activity probe as a readout in a high-throughput live-cell fluorescence-activated cell sorting-based assay revealed more than ten compounds that increase proteasome activity, with the p38 MAPK inhibitor PD169316 being one of the most potent ones. Genetic and chemical inhibition of either p38 MAPK, its upstream regulators, ASK1 and MKK6, and downstream target, MK2, enhance proteasome activity. Chemical activation of the 26S proteasome increases PROTAC-mediated and ubiquitin-dependent protein degradation and decreases the levels of both overexpressed and endogenous α-synuclein, without affecting the overall protein turnover. In addition, survival of cells overexpressing toxic α-synuclein assemblies is increased in the presence of p38 MAPK inhibitors. These findings highlight the potential of activation of 26S proteasome activity and that this can be achieved through multiple mechanisms by distinct molecules.",

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AU - Zaal, Esther A

AU - van de Kooij, Bert

AU - Laufer, Stefan

AU - Heck, Albert J R

AU - Borst, Jannie

AU - Scheper, Wiep

AU - Berkers, Celia R

AU - Ovaa, Huib

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Proteasome Activation by Small Molecules

Abstract

Funding

Keywords

UN SDGs

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