Compromising the 19S proteasome complex protects cells from reduced flux through the proteasome

被引：67

作者：

Tsvetkov, Peter ^{[1
]}

Mendillo, Marc L. ^{[2
]}

Zhao, Jinghui ^{[3
]}

Carette, Jan E. ^{[4
]}

Merrill, Parker H. ^{[5
]}

Cikes, Domagoj ^{[6
]}

Varadarajan, Malini ^{[1
]}

van Diemen, Ferdy R. ^{[7
]}

Penninger, Josef M. ^{[6
]}

Goldberg, Alfred L. ^{[3
]}

Brummelkamp, Thijn R. ^{[7
]}

Santagata, Sandro ^{[1
,8
,9
]}

Lindquist, Susan ^{[1
,2
]}

机构：

[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA

[2] MIT, Howard Hughes Med Inst, Dept Biol, Cambridge, MA 02139 USA

[3] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA USA

[4] Stanford Univ, Dept Microbiol & Immunol, Sch Med, Stanford, CA 94305 USA

[5] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Pathol, Boston, MA 02115 USA

[6] Austrian Acad Sci, Inst Mol Biotechnol, A-1010 Vienna, Austria

[7] Netherlands Canc Inst, Dept Biochem, Amsterdam, Netherlands

[8] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[9] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

来源：

ELIFE | 2015年 / 4卷

基金：

美国国家卫生研究院;

关键词：

26S PROTEASOME; 20S PROTEASOME; HEAT-SHOCK; DEGRADATION; INHIBITORS; GENE; IDENTIFICATION; PROTEOSTASIS; TRANSLATION; TRANSPORTER;

D O I：

10.7554/eLife.08467

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Proteasomes are central regulators of protein homeostasis in eukaryotes. Proteasome function is vulnerable to environmental insults, cellular protein imbalance and targeted pharmaceuticals. Yet, mechanisms that cells deploy to counteract inhibition of this central regulator are little understood. To find such mechanisms, we reduced flux through the proteasome to the point of toxicity with specific inhibitors and performed genome-wide screens for mutations that allowed cells to survive. Counter to expectation, reducing expression of individual subunits of the proteasome's 19S regulatory complex increased survival. Strong 19S reduction was cytotoxic but modest reduction protected cells from inhibitors. Protection was accompanied by an increased ratio of 20S to 26S proteasomes, preservation of protein degradation capacity and reduced proteotoxic stress. While compromise of 19S function can have a fitness cost under basal conditions, it provided a powerful survival advantage when proteasome function was impaired. This means of rebalancing proteostasis is conserved from yeast to humans.

引用

页数：22

共 79 条

[41] Molecular Mechanisms of Acquired Proteasome Inhibitor Resistance [J].