Venuprasad K, Huang Haining, Harada Yousuke, Elly Chris, Subramaniam Malayannan, Spelsberg Thomas, Su Jin, Liu Yun-Cai
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.
Nat Immunol. 2008 Mar;9(3):245-53. doi: 10.1038/ni1564. Epub 2008 Feb 17.
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.
在初始T细胞中，转化生长因子-β（TGF-β）信号传导可诱导转录因子Foxp3的表达，Foxp3是调节性T细胞（Treg细胞）的“主”调节因子。然而，导致Foxp3诱导的分子机制仍不清楚。在此我们表明，缺失Itch的T细胞对TGF-β处理具有抗性，且Foxp3表达较少。E3泛素连接酶Itch与转录因子TIEG1结合并促进泛素与TIEG1的缀合。Itch与TIEG1协同诱导Foxp3表达，而TIEG1缺陷可逆转这种诱导作用。在功能上，由TIEG1缺陷小鼠产生的“TGF-β转化”Treg细胞在体内无法抑制气道炎症。这些结果表明，TIEG和Itch促成了一条依赖泛素的非蛋白水解途径，该途径调节诱导性Foxp3表达及过敏反应的控制。
