FasL Expression in Activated T Lymphocytes Involves HuR-mediated Stabilization
FasL Expression in Activated T Lymphocytes Involves HuR-mediated Stabilization
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DOI：
10.1074/jbc.m110.137919
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发表时间：
2010-10-08
影响因子：
4.8
通讯作者：
Gallouzi, Imed-Eddine
中科院分区：
文献类型：
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作者：
Drury, Gillian L.;Di Marco, Sergio;Gallouzi, Imed-Eddine
免疫系统的长期激活是导致免疫耐受缺陷和自身免疫性疾病的淋巴细胞过度增殖的主要原因之一。Fas配体（FasL）是TNF超家族的一员，通过诱导T细胞凋亡导致其快速消除，在控制这种过度淋巴细胞增殖中起着至关重要的作用。在这里，我们建立了转录后调控的分子机制，调节FasL的表达，我们表明，在活化的T细胞FasL mRNA是稳定的。我们的序列分析表明，FasL的3 '-非翻译区（UTR）包含两个AU丰富的元件（战神），在序列和结构上类似于那些存在于TNF-α mRNA的3'-UTR。通过这些战神，FasL mRNA在体外和离体都与RNA结合蛋白HuR形成复合物。敲低HEK 293细胞中的HuR阻止了佛波醇12-肉豆蔻酸酯13-乙酸酯诱导的与FasL 3 '-UTR融合的GFP报告构建体的表达。总的来说，我们的数据表明，FasL mRNA的转录后调节HuR代表了一种新的机制，可以发挥关键作用，在维护和正常运作的免疫系统。
A prolonged activation of the immune system is one of the main causes of hyperproliferation of lymphocytes leading to defects in immune tolerance and autoimmune diseases. Fas ligand (FasL), a member of the TNF superfamily, plays a crucial role in controlling this excessive lymphoproliferation by inducing apoptosis in T cells leading to their rapid elimination. Here, we establish that posttranscriptional regulation is part of the molecular mechanisms that modulate FasL expression, and we show that in activated T cells FasL mRNA is stable. Our sequence analysis indicates that the FasL 3'-untranslated region (UTR) contains two AU-rich elements (AREs) that are similar in sequence and structure to those present in the 3'-UTR of TNF-alpha mRNA. Through these AREs, the FasL mRNA forms a complex with the RNA-binding protein HuR both in vitro and ex vivo. Knocking down HuR in HEK 293 cells prevented the phorbol 12-myristate 13-acetate-induced expression of a GFP reporter construct fused to the FasL 3'-UTR. Collectively, our data demonstrate that the posttranscriptional regulation of FasL mRNA by HuR represents a novel mechanism that could play a key role in the maintenance and proper functioning of the immune system.