Abstract
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.
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Acknowledgements
We thank J.L. Bos and L. Price for critically reading the manuscript; the members of the Bos and Burgering labs for helpful discussions; T. Kerppola., J. Rodriguez, A. Borodovsky and D. Bohmann for kindly providing DNA constructs; and B. Kumar and J. van der Knaap for supplying purified USP7. The authors also acknowledge H. Ovaa for providing the HA–ubiquitin probe and Hybrigenics staff for their contributions. This work was supported by grants from the Dutch Cancer Society (KWF, UU-2001-2438) to A.v.d.H.; from The Netherlands organization for scientific research (NWO, Zon-MW 906-02-041) to M.M.M.; from the Cancer Genomics center to N.v.d.B.; and from the European Commission Transfog Consortium (LSHC-CT-2004-503438) to A.B.B.
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A.v.d.H., A.M.M.d.V-S. and B.M.T.B. conceived and designed the expermiments. A.v.d.H., A.M.M.d.V-S., A.B.B., M.H.v.T. and N.v.d.B performed the experiments. F.C. and M.M.M. contributed essential materials. A.v.d.H., A.M.M.d.V-S. and B.M.T.B analysed the data. A.v.d.H. and B.M.T.B wrote the paper.
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van der Horst, A., de Vries-Smits, A., Brenkman, A. et al. FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nat Cell Biol 8, 1064–1073 (2006). https://doi.org/10.1038/ncb1469
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DOI: https://doi.org/10.1038/ncb1469
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