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FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP.

FOXO (Forkhead box O) transcription factors are important regulators of cellular metabolism, cell-cycle progression and cell death. FOXO activity is regulated by multiple post-translational modifications, including phosphorylation, acetylation and polyubiquitination. Here, we show that FOXO becomes monoubiquitinated in response to increased cellular oxidative stress, resulting in its re-localization to the nucleus and an increase in its transcriptional activity. Deubiquitination of FOXO requires the deubiquitinating enzyme USP7/HAUSP (herpesvirus-associated ubiquitin-specific protease), which interacts with and deubiquitinates FOXO in response to oxidative stress. Oxidative stress-induced ubiquitination and deubiquitination by USP7 do not influence FOXO protein half-life. However, USP7 does negatively regulate FOXO transcriptional activity towards endogenous promoters. Our results demonstrate a novel mechanism of FOXO regulation and indicate that USP7 has an important role in regulating FOXO-mediated stress responses.

Pubmed ID: 16964248


  • van der Horst A
  • de Vries-Smits AM
  • Brenkman AB
  • van Triest MH
  • van den Broek N
  • Colland F
  • Maurice MM
  • Burgering BM


Nature cell biology

Publication Data

October 2, 2006

Associated Grants


Mesh Terms

  • Animals
  • Cells, Cultured
  • Endopeptidases
  • Gene Expression Regulation
  • Humans
  • Hydrogen Peroxide
  • Kidney
  • Lung Neoplasms
  • Mice
  • NIH 3T3 Cells
  • Oxidants
  • Oxidative Stress
  • Protein Processing, Post-Translational
  • RNA, Messenger
  • Transcription Factors
  • Transcription, Genetic
  • Transfection
  • Ubiquitin
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases