TY - JOUR
T1 - Ubiquitin-recognition protein Ufd1 couples the endoplasmic reticulum (ER) stress response to cell cycle control
AU - Chen, Meifan
AU - Gutierrez, Gustavo J.
AU - Ronai, Ze'ev A.
PY - 2011/5/31
Y1 - 2011/5/31
N2 - 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/CCdh1), 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/CCdh1-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.
AB - 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/CCdh1), 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/CCdh1-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.
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U2 - 10.1073/pnas.1100028108
DO - 10.1073/pnas.1100028108
M3 - Article
C2 - 21571647
AN - SCOPUS:79959335295
SN - 0027-8424
VL - 108
SP - 9119
EP - 9124
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 22
ER -