Coordinate regulation of GATA-3 and Th2 cytokine gene expression by the RNA-binding protein HuR.
Coordinate regulation of GATA-3 and Th2 cytokine gene expression by the RNA-binding protein HuR.
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DOI：
10.4049/jimmunol.1001881
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发表时间：
2011-07-01
期刊：
影响因子：
--
通讯作者：
Atasoy U
中科院分区：
文献类型：
--
作者：
Stellato C;Gubin MM;Magee JD;Fang X;Fan J;Tartar DM;Chen J;Dahm GM;Calaluce R;Mori F;Jackson GA;Casolaro V;Franklin CL;Atasoy U
RNA结合蛋白(RBPs)调控T细胞分化的转录后机制尚不清楚。限制性商业惯例可以通过与共同的调控序列结合来协调调节功能相关基因的表达，例如存在于mRNA3‘非翻译区的富含腺苷尿苷的元件(ARE)。RBP HUR在转录后调节IL-4、IL-13和其他Th2细胞限制性转录本。我们假设，携带ARE的GATA-3基因是Th2极化的关键调节因子，受Hur控制，作为其对Th2程序的协调转录后调节的一部分。我们报道，在刺激诱导GATA-3mRNA和蛋白水平增加的同时，在人类T细胞系Jurkat、人类记忆细胞和Th2细胞以及小鼠Th2偏斜细胞中，重新刺激后GATA-3mRNA半衰期增加。我们通过免疫沉淀核糖核蛋白复合体证明了Hur与人T细胞中的GATA-3内源性转录本相关，并通过生物素下拉试验发现Hur与其3‘UTR特异地相互作用。在体外和动物模型中，使用功能丧失和功能获得的方法，我们证明HUR是刺激诱导的GATA-3mRNA和蛋白表达增加的关键中介，它积极地影响GATA-3mRNA的周转，同时选择性地促进Th2细胞因子的过度表达。这些结果表明，在小鼠和人类系统中，HUR驱动的转录后调控在T细胞的发育和效应器功能中都发挥着重要作用。更好地了解HUR介导的Th2极化控制可能有助于改变人类哮喘患者的过敏性呼吸道炎症。
The posttranscriptional mechanisms whereby RNA-binding proteins (RBPs) regulate T cell differentiation remain unclear. RBPs can coordinately regulate the expression of functionally related genes via binding to shared regulatory sequences, such as the Adenylate-Uridylate-Rich Elements (ARE) present in mRNA’s 3′ untranslated region (UTR). The RBP HuR posttranscriptionally regulates IL-4, IL-13 and other Th2-cell-restricted transcripts. We hypothesized that the ARE-bearing GATA-3 gene, a critical regulator of Th2 polarization, is under HuR control as part of its coordinate posttranscriptional regulation of the Th2 program. We report that in parallel with stimulus-induced increase in GATA-3 mRNA and protein levels, GATA-3 mRNA half-life is increased after restimulation in the human T cell line Jurkat, in human memory and Th2 cells and in murine Th2-skewed cells. We demonstrate by immunoprecipitation of ribonucleoprotein complexes that HuR associates with the GATA-3 endogenous transcript in human T cells and found, using biotin pull-down assay, that HuR specifically interacts with its 3′UTR. Using both loss- and gain-of-function approaches in vitro and in animal models, we show that HuR is a critical mediator of stimulus-induced increase in GATA-3 mRNA and protein expression and that it positively influences GATA-3 mRNA turnover, in parallel with selective promotion of Th2 cytokine overexpression. These results suggest that HuR-driven posttranscriptional control plays a significant role in T cell development and effector function in both murine and human systems. A better understanding of HuR-mediated control of Th2 polarization may have utility in altering allergic airway inflammation in human asthmatic patients.
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影响因子：
64.5
作者：
Kouros-Mehr, Hosein;Slorach, Euan M.;Werb, Zena
通讯作者：
Werb, Zena
影响因子：
50.3
作者：
Kouros-Mehr, Hosein;Bechis, Seth K.;Werb, Zena
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Werb, Zena
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作者：
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影响因子：
14.2
作者：
Casolaro, Vincenzo;Fang, Xi;Stellato, Cristiana
通讯作者：
Stellato, Cristiana
影响因子：
3.8
作者：
Calaluce R;Gubin MM;Davis JW;Magee JD;Chen J;Kuwano Y;Gorospe M;Atasoy U
通讯作者：
Atasoy U