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FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP

Nature Cell Biology volume 8, pages 1064–1073 (2006)Cite this article

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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Figure 1: Hydrogen peroxide induces monoubiquitination of FOXO4.
Figure 2: Effects of monoubiquitination on FOXO4.
Figure 3: USP7 interacts with and deubiquitinates FOXO4.
Figure 4: FOXO4 monoubiquitination precedes USP7 binding to FOXO4.
Figure 5: USP7 regulates FOXO transcriptional activity.
Figure 6: A model illustrating how oxidative stress regulates FOXO transcriptional activity through ubiquitination and acetylation.

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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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Authors and Affiliations

  1. Department of Physiological Chemistry, Centre for Biomedical Genetics, University Medical Center Utrecht, Utrecht, 3584 CG, The Netherlands

    Armando van der Horst, Alida M.M. de Vries-Smits, Arjan B. Brenkman, Miranda H. van Triest, Niels van den Broek & Boudewijn M.T. Burgering

  2. Hybrigenics SA, 3-5 Impasse Reille, Paris, 75014, France

    Frédéric Colland

  3. Department of Cell Biology, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands

    Madelon M. Maurice

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  1. Armando van der Horst
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Contributions

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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Correspondence to Boudewijn M.T. Burgering.

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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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