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

• Published in: Nature immunology Vol. 9; no. 3; pp. 245 - 253
• Main Authors: Spelsberg, Thomas, Elly, Chris, Subramaniam, Malayannan, Liu, Yun-Cai, Su, Jin, Venuprasad, K, Huang, Haining, Harada, Yousuke
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2008; Nature Publishing Group
• Subjects: Allergic reaction; Allergy; Animals; Biomedical and Life Sciences; Biomedicine; Cells, Cultured; Control; Development and progression; Disease Models, Animal; DNA binding proteins; Early Growth Response Transcription Factors - physiology; Forkhead Transcription Factors - metabolism; Gene Expression Regulation - immunology; Genetic aspects; Hypersensitivity - immunology; Immunology; Infectious Diseases; Inflammation - immunology; Kruppel-Like Transcription Factors - physiology; Ligases; Mice; Mice, Inbred C57BL; Mice, Knockout; Physiological aspects; Properties; Repressor Proteins - genetics; Repressor Proteins - physiology; Respiratory System - immunology; Signal Transduction - immunology; Th2 Cells - immunology; Transfection; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - physiology; United States
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni1564

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 (T reg 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' T reg 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.