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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-05, Vol.108 (22), p.9119-9124
• Main Authors: Chen, Meifan, Gutierrez, Gustavo J, Ronai, Ze'ev A
• Format: Article
• Language: English
• Subjects: Abiotic stress; Anaphase-promoting complex; Binding Sites; Biological Sciences; CDH1 protein; Cell Cycle; Cell cycle proteins; Cell lines; Cell Separation; cyclin-dependent kinase; Cyclin-dependent kinase inhibitor p27; Cyclins; Data processing; Down regulation; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Enzymes; Flow Cytometry; G1 phase; Gene expression; Gene Expression Regulation, Fungal; HeLa Cells; Humans; interphase; Misfolded proteins; Mutation; Physiological regulation; Protein folding; Protein Structure, Tertiary; Proteins; Proteins - metabolism; Proteins - physiology; S phase kinase associated proteins; S-Phase Kinase-Associated Proteins - metabolism; Saccharomyces cerevisiae - metabolism; Skp2 protein; Stress; stress response; Tunicamycin - pharmacology; ubiquitination; Ubiquitins
• ISSN: 0027-8424; 1091-6490
• 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/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.