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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

Venuprasad K, Huang H, Harada Y +5 more2008Nature ImmunologyJournal Article
10.1038/ni1564PubMed
Immune/InnateRespiratory/Sinus

Abstract

Transforming growth factor-beta (TGF-beta) 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-beta 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-beta-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.

Key Biomarkers

Foxp3Itch E3 ubiquitin ligaseRegulatory T cellsTGF-beta signalingTIEG1

Symptom Clusters

Airway inflammationAllergic responses

Cited By (2)

  • Epigenetic mechanisms of regulation of FoxP3 expressionBlood · 2009
  • Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage?Nature reviews. Immunology · 2009

References (3)

  • Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor Foxp3The Journal of Experimental Medicine · 2003
  • Foxp3-dependent and –independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysisInternational Immunology · 2006
  • Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory diseaseNature · 1992

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