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The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1

Nature Immunology volume 9, pages 245–253 (2008)Cite this article

Abstract

Transforming growth factor-β (TGF-β) signaling in naive T cells induces expression of the transcription factor Foxp3, a 'master' regulator of regulatory T cells (Treg cells). However, the molecular mechanisms leading to Foxp3 induction remain unclear. Here we show that Itch−/− T cells were resistant to TGF-β treatment and had less Foxp3 expression. The E3 ubiquitin ligase Itch associated with and promoted conjugation of ubiquitin to the transcription factor TIEG1. Itch cooperated with TIEG1 to induce Foxp3 expression, which was reversed by TIEG1 deficiency. Functionally, 'TGF-β-converted' Treg cells generated from TIEG1-deficient mice were unable to suppress airway inflammation in vivo. These results suggest TIEG and Itch contribute to a ubiquitin-dependent nonproteolytic pathway that regulates inducible Foxp3 expression and the control of allergic responses.

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Figure 1: Itch−/− CD4+CD25− cells are resistant to TGF-β-mediated suppression.
Figure 2: Itch regulates Foxp3 expression in TGF-β-treated CD4+CD25− cells.
Figure 3: Itch associates with TIEG1 and targets it for ubiquitination.
Figure 4: Itch-mediated ubiquitination of TIEG1 is necessary for Foxp3 expression.
Figure 5: TIEG1 expression restores Foxp3 expression in Itch−/− T cells.
Figure 6: TIEG1-deficient T cells fail to express Foxp3.
Figure 7: Reconstitution of TIEG1 restores Foxp3 expression.
Figure 8: TIEG1-deficient Treg cells are defective in inhibiting airway inflammation.

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Acknowledgements

We thank W. Zhang (Duke University) for providing Foxp3 retroviral vector, and J. Huehn (Charite University) for the Foxp3-luciferase reporter plasmid. Supported by the National Institutes of Health (Y.-C.L.).

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Authors and Affiliations

  1. Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, 92037, California, USA

    K Venuprasad, Haining Huang, Yousuke Harada, Chris Elly, Jin Su & Yun-Cai Liu

  2. Mayo Clinic and Foundation, Rochester, 55905, Minnesota, USA

    Malayannan Subramaniam & Thomas Spelsberg

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  1. K Venuprasad
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Contributions

K.V. contributed to the design and execution of the experiments and data interpretation and helped prepare the manuscript; H.H., Y.H., C.E. and J.S. did the molecular and biochemical experiments and provided technical assistance; S.M. and T.S. provided mice; and Y.-C.L. supervised the project and helped prepare the manuscript.

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Correspondence to Yun-Cai Liu.

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Venuprasad, K., Huang, H., Harada, Y. et al. The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1. Nat Immunol 9, 245–253 (2008). https://doi.org/10.1038/ni1564

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