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Proc Natl Acad Sci U S A. 2011 May 31;108(22):9119-24. doi: 10.1073/pnas.1100028108. Epub 2011 May 13.

Ubiquitin-recognition protein Ufd1 couples the endoplasmic reticulum (ER) stress response to cell cycle control.

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1
Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.

Abstract

The ubiquitin-recognition protein Ufd1 facilitates clearance of misfolded proteins through the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. Here we report that prolonged ER stress represses Ufd1 expression to trigger cell cycle delay, which contributes to ERAD. Remarkably, down-regulation of Ufd1 enhances ubiquitination and destabilization of Skp2 mediated by the anaphase-promoting complex or cyclosome bound to Cdh1 (APC/C(Cdh1)), resulting in accumulation of the cyclin-dependent kinase inhibitor p27 and a concomitant cell cycle delay during the G1 phase that enables more efficient clearance of misfolded proteins. Mechanistically, nuclear Ufd1 recruits the deubiquitinating enzyme USP13 to counteract APC/C(Cdh1)-mediated ubiquitination of Skp2. Our data identify a coordinated cell cycle response to prolonged ER stress through regulation of the Cdh1-Skp2-p27 axis by Ufd1 and USP13.

PMID:
21571647
PMCID:
PMC3107271
DOI:
10.1073/pnas.1100028108
[Indexed for MEDLINE]
Free PMC Article
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