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

作者：Chen Meifan; Gutierrez Gustavo J; Ronai Ze'ev A^*

来源：Proceedings of the National Academy of Sciences, 2011, 108(22): 9119-9124.

DOI：10.1073/pnas.1100028108

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.

• 出版日期2011-5-31