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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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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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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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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DOI: https://doi.org/10.1038/ni1564