TAG, a splice variant of the adaptor TRAM, negatively regulates the adaptor MyD88-independent TLR4 pathway
TAG, a splice variant of the adaptor TRAM, negatively regulates the adaptor MyD88-independent TLR4 pathway
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DOI：
10.1038/ni.1727
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发表时间：
2009-06-01
影响因子：
30.5
通讯作者：
O'Neill, Luke A. J.
中科院分区：
文献类型：
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作者：
Palsson-McDermott, Eva M.;Doyle, Sarah L.;O'Neill, Luke A. J.
Toll样受体4（TLR 4）通过接头TRAM从早期内体发出诱导转录因子IRF 3依赖性基因的信号。在这里，我们报告了TRAM的剪接变体，TAG（“TRAM适配器与黄金域”），它有一个高尔基体动力学结构域耦合到TRAM的Toll-白细胞介素1受体结构域。在用脂多糖刺激后，TRAM和TAG定位于对GTCRab 7a呈阳性的晚期内体。TAG抑制脂多糖对IRF 3的激活。在人外周血单核细胞中，用小干扰RNA敲低TAG增强了脂多糖对趋化因子CCL 5（RANTES）的诱导，但不增强对白细胞介素8的诱导。TAG取代了TRAM中的适配器TRIF。TAG因此是由TLR 4激活的衔接子MyD 88非依赖性途径的特异性抑制剂的实例。靶向TAG可能有助于增强TLR 4的免疫刺激作用，而不会引起不必要的炎症。
Toll-like receptor 4 (TLR4) signals the induction of transcription factor IRF3-dependent genes from the early endosome via the adaptor TRAM. Here we report a splice variant of TRAM, TAG ('TRAM adaptor with GOLD domain'), which has a Golgi dynamics domain coupled to TRAM's Toll-interleukin 1 receptor domain. After stimulation with lipopolysaccharide, TRAM and TAG localized to late endosomes positive for the GTPase Rab7a. TAG inhibited activation of IRF3 by lipopolysaccharide. Knockdown of TAG with small interfering RNA enhanced induction of the chemokine CCL5 (RANTES), but not of interleukin 8, by lipopolysaccharide in human peripheral blood mononuclear cells. TAG displaced the adaptor TRIF from TRAM. TAG is therefore an example of a specific inhibitor of the adaptor MyD88-independent pathway activated by TLR4. Targeting TAG could be useful in the effort to boost the immunostimulatory effect of TLR4 without causing unwanted inflammation.