Coordinate regulation of GATA-3 and Th2 cytokine gene expression by the RNA-binding protein HuR

Cristiana Stellato, Matthew M. Gubin, Joseph D. Magee, Xi Fang, Jinshui Fan, Danielle Tartar, Jing Chen, Garrett M. Dahm, Robert Calaluce, Francesca Mori, Glenn A. Jackson, Vincenzo Casolaro, Craig L. Franklin, Ulus Atasoy

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 39UTR. 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.

Original languageEnglish (US)
Pages (from-to)441-449
Number of pages9
JournalJournal of Immunology
Volume187
Issue number1
DOIs
StatePublished - Jul 1 2011
Externally publishedYes

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RNA-Binding Proteins
Th2 Cells
Cytokines
Gene Expression
Messenger RNA
T-Lymphocytes
Ribonucleoproteins
Interleukin-13
3' Untranslated Regions
Biotin
Immunoprecipitation
Interleukin-4
Genes
Half-Life
Cell Differentiation
Proteins
Animal Models
Inflammation
Cell Line

ASJC Scopus subject areas

  • Immunology

Cite this

Coordinate regulation of GATA-3 and Th2 cytokine gene expression by the RNA-binding protein HuR. / Stellato, Cristiana; Gubin, Matthew M.; Magee, Joseph D.; Fang, Xi; Fan, Jinshui; Tartar, Danielle; Chen, Jing; Dahm, Garrett M.; Calaluce, Robert; Mori, Francesca; Jackson, Glenn A.; Casolaro, Vincenzo; Franklin, Craig L.; Atasoy, Ulus.

In: Journal of Immunology, Vol. 187, No. 1, 01.07.2011, p. 441-449.

Research output: Contribution to journalArticle

Stellato, C, Gubin, MM, Magee, JD, Fang, X, Fan, J, Tartar, D, Chen, J, Dahm, GM, Calaluce, R, Mori, F, Jackson, GA, Casolaro, V, Franklin, CL & Atasoy, U 2011, 'Coordinate regulation of GATA-3 and Th2 cytokine gene expression by the RNA-binding protein HuR', Journal of Immunology, vol. 187, no. 1, pp. 441-449. https://doi.org/10.4049/jimmunol.1001881
Stellato, Cristiana ; Gubin, Matthew M. ; Magee, Joseph D. ; Fang, Xi ; Fan, Jinshui ; Tartar, Danielle ; Chen, Jing ; Dahm, Garrett M. ; Calaluce, Robert ; Mori, Francesca ; Jackson, Glenn A. ; Casolaro, Vincenzo ; Franklin, Craig L. ; Atasoy, Ulus. / Coordinate regulation of GATA-3 and Th2 cytokine gene expression by the RNA-binding protein HuR. In: Journal of Immunology. 2011 ; Vol. 187, No. 1. pp. 441-449.
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AU - Fan, Jinshui

AU - Tartar, Danielle

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AU - Dahm, Garrett M.

AU - Calaluce, Robert

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AU - Franklin, Craig L.

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