1. Proteasome Activation by Small Molecules
- Author
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Leestemaker, Yves, de Jong, Annemieke, Witting, Katharina F, Penning, Renske, Schuurman, Karianne, Rodenko, Boris, Zaal, Esther A, van de Kooij, Bert, Laufer, Stefan, Heck, Albert J R, Borst, Jannie, Scheper, Wiep, Berkers, Celia R, Ovaa, Huib, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Biomolecular Mass Spectrometry and Proteomics, Functional Genomics, Afd Biomol.Mass Spect. and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., and Biomolecular Mass Spectrometry and Proteomics
- Subjects
0301 basic medicine ,Proteasome Endopeptidase Complex ,p38 mitogen-activated protein kinases ,Proteolysis ,Clinical Biochemistry ,Biology ,Biochemistry ,p38 Mitogen-Activated Protein Kinases ,Cell Line ,03 medical and health sciences ,Enzyme activator ,SDG 3 - Good Health and Well-being ,Cell Line, Tumor ,Drug Discovery ,medicine ,Journal Article ,Humans ,ASK1 ,Molecular Biology ,Pharmacology ,Tumor ,medicine.diagnostic_test ,Activity-based proteomics ,Protein turnover ,Imidazoles ,Cell biology ,Enzyme Activation ,030104 developmental biology ,Proteasome ,Molecular Medicine ,Chemical genetics ,Proteasome Inhibitors - 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.
- Published
- 2016
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