A Ribosome-Bound Quality Control Complex Triggers Degradation of Nascent Peptides and Signals Translation Stress

被引：463

作者：

Brandman, Onn ^{[5
,6
,8
]}

Stewart-Ornstein, Jacob ^{[5
,6
,8
]}

Wong, Daisy ^{[5
,6
,8
]}

Larson, Adam ^{[7
]}

Williams, Christopher C. ^{[5
,6
,8
]}

Li, Gene-Wei ^{[5
,6
,8
]}

Zhou, Sharleen ^{[4
]}

King, David ^{[4
]}

Shen, Peter S. ^{[1
,2
]}

Weibezahn, Jimena ^{[5
,6
,8
]}

Dunn, Joshua G. ^{[5
,6
,8
]}

Rouskin, Silvi ^{[5
,6
,8
]}

Inada, Toshifumi ^{[3
]}

Frost, Adam ^{[1
,2
]}

Weissman, Jonathan S. ^{[5
,6
,8
]}

机构：

[1] Univ Utah, Sch Med, Dept Biochem, Salt Lake City, UT 84112 USA

[2] Univ Utah, Sch Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA

[3] Tohoku Univ, Grad Sch Pharmaceut Sci, Sendai, Miyagi 9808578, Japan

[4] Univ Calif Berkeley, HHMI Mass Spectrometry Lab, Berkeley, CA 94720 USA

[5] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94158 USA

[6] Univ Calif San Francisco, Calif Inst Quantitat Biomed Res, San Francisco, CA 94158 USA

[7] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA

[8] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94158 USA

来源：

CELL | 2012年 / 151卷 / 05期

关键词：

HEAT-SHOCK FACTOR-1; GENOME-WIDE ANALYSIS; PROTEIN; SURVEILLANCE; ELONGATION; ACTIVATION; CHAPERONES; BINDING; SYSTEM; ER;

D O I：

10.1016/j.cell.2012.10.044

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：

The conserved transcriptional regulator heat shock factor 1 (Hsf1) is a key sensor of proteotoxic and other stress in the eukaryotic cytosol. We surveyed Hsf1 activity in a genome-wide loss-of-function library in Saccaromyces cerevisiae as well as similar to 78,000 double mutants and found Hsf1 activity to be modulated by highly diverse stresses. These included disruption of a ribosome-bound complex we named the Ribosome Quality Control Complex (RQC) comprising the Ltn1 E3 ubiquitin ligase, two highly conserved but poorly characterized proteins (Tae2 and Rqc1), and Cdc48 and its cofactors. Electron microscopy and biochemical analyses revealed that the RQC forms a stable complex with 60S ribosomal subunits containing stalled polypeptides and triggers their degradation. A negative feedback loop regulates the RQC, and Hsf1 senses an RQC-mediated translation-stress signal distinctly from other stresses. Our work reveals the range of stresses Hsf1 monitors and elucidates a conserved cotranslational protein quality control mechanism.

引用

页码：1042 / 1054

页数：13

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