title: Coordinate regulation of GATA-3 and Th2 cytokine gene expression by the RNA-binding protein HuR.
abstract: 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 (AREs) present in the 3' untranslated region (UTR) of mRNA. 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 pulldown assay, that HuR specifically interacts with its 3'UTR. Using both loss-of-function 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.
authors: Division of Allergy and Clinical Immunology, The Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
authors: Cristiana
authors: C
authors: Stellato
authors: Matthew M
authors: MM
authors: Gubin
authors: Joseph D
authors: JD
authors: Magee
authors: Xi
authors: X
authors: Fang
authors: Jinshui
authors: J
authors: Fan
authors: Danielle M
authors: DM
authors: Tartar
authors: Jing
authors: J
authors: Chen
authors: Garrett M
authors: GM
authors: Dahm
authors: Robert
authors: R
authors: Calaluce
authors: Francesca
authors: F
authors: Mori
authors: Glenn A
authors: GA
authors: Jackson
authors: Vincenzo
authors: V
authors: Casolaro
authors: Craig L
authors: CL
authors: Franklin
authors: Ulus
authors: U
authors: Atasoy
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