Proteasome Activation by Small Molecules

被引：115

作者：

Leestemaker, Yves ^{[1
,2
]}

de Jong, Annemieke ^{[1
]}

Witting, Katharina F. ^{[1
,2
]}

Penning, Renske ^{[3
]}

Schuurman, Karianne ^{[1
,9
]}

Rodenko, Boris ^{[1
,10
]}

Zaal, Esther A. ^{[3
]}

van de Kooij, Bert ^{[4
]}

Laufer, Stefan ^{[5
]}

Heck, Albert J. R. ^{[3
]}

Borst, Jannie ^{[4
]}

Scheper, Wiep ^{[6
,7
,8
]}

Berkers, Celia R. ^{[3
]}

Ovaa, Huib ^{[1
,2
]}

机构：

[1] Netherlands Canc Inst, Div Cell Biol 2, NL-1066 CX Amsterdam, Netherlands

[2] Leiden Univ, Med Ctr, Dept Chem Immunol, NL-2300 RC Leiden, Netherlands

[3] Univ Utrecht, Biomol Mass Spectrometry & Prote, NL-3584 CH Utrecht, Netherlands

[4] Netherlands Canc Inst, Div Immunol, NL-2300 RC Amsterdam, Netherlands

[5] Univ Tubingen, Inst Pharm, D-72076 Tubingen, Germany

[6] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands

[7] Vrije Univ Amsterdam, Med Ctr, Alzheimer Ctr, Amsterdam, Netherlands

[8] Vrije Univ Amsterdam, Dept Funct Genome Anal, NL-1081 HV Amsterdam, Netherlands

[9] Netherlands Canc Inst, Div Mol Pathol, NL-2300 RC Amsterdam, Netherlands

[10] UbiQ Bio BV, NL-1098 XH Amsterdam, Netherlands

来源：

CELL CHEMICAL BIOLOGY | 2017年 / 24卷 / 06期

关键词：

ALPHA-SYNUCLEIN; PROTEIN-KINASE; IN-VIVO; 26S PROTEASOME; TAU PHOSPHORYLATION; HUNTINGTONS-DISEASE; PARKINSONS-DISEASE; LATERAL-SCLEROSIS; LIVING CELLS; DEGRADATION;

D O I：

10.1016/j.chembiol.2017.05.010

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 down-stream 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 alpha-synuclein, without affecting the overall protein turnover. In addition, survival of cells overexpressing toxic alpha-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.

引用

页码：725 / +

页数：19

共 53 条

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