Ubiquitin-recognition protein Ufd1 couples the endoplasmic reticulum (ER) stress response to cell cycle control.
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.
Mesh Terms:
Binding Sites, Cell Cycle, Cell Separation, Down-Regulation, Endoplasmic Reticulum, Flow Cytometry, Gene Expression Regulation, Fungal, Hela Cells, Humans, Mutation, Protein Structure, Tertiary, Proteins, S-Phase Kinase-Associated Proteins, Saccharomyces cerevisiae, Tunicamycin
Binding Sites, Cell Cycle, Cell Separation, Down-Regulation, Endoplasmic Reticulum, Flow Cytometry, Gene Expression Regulation, Fungal, Hela Cells, Humans, Mutation, Protein Structure, Tertiary, Proteins, S-Phase Kinase-Associated Proteins, Saccharomyces cerevisiae, Tunicamycin
Proc. Natl. Acad. Sci. U.S.A.
Date: May. 31, 2011
PubMed ID: 21571647
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