title: Ubiquitin-recognition protein Ufd1 couples the endoplasmic reticulum (ER) stress response to cell cycle control.
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.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Meifan
authors.initials: M
authors.lastname: Chen
authors.forename: Gustavo J
authors.initials: GJ
authors.lastname: Gutierrez
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D001665:Binding Sites; D002453:Cell Cycle; D002469:Cell Separation; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005434:Flow Cytometry; D015966:Gene Expression Regulation, Fungal; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D044786:S-Phase Kinase-Associated Proteins; C491497:UFD1 protein, human; D014415:Tunicamycin