The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1.
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.
Venuprasad
K
K
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
Huang
Haining
H
Harada
Yousuke
Y
Elly
Chris
C
Subramaniam
Malayannan
M
Spelsberg
Thomas
T
Su
Jin
J
Liu
Yun-Cai
YC
D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D051765:Early Growth Response Transcription Factors / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D006967:Hypersensitivity / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D012137:Respiratory System / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
D051765:Early Growth Response Transcription Factors; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C098111:KLF10 protein, human; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases