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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.

Pubmed ID: 21571647

Authors

  • Chen M
  • Gutierrez GJ
  • Ronai ZA

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

May 31, 2011

Associated Grants

  • Agency: NCI NIH HHS, Id: 5T32CA077109
  • Agency: NCI NIH HHS, Id: CA097105
  • Agency: NCI NIH HHS, Id: CA78419
  • Agency: NCI NIH HHS, Id: P30 CA030199
  • Agency: NCI NIH HHS, Id: R01 CA138143

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