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Originally published online as doi:10.1189/jlb.0206120 on May 14, 2007

Published online before print May 14, 2007
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(Journal of Leukocyte Biology. 2007;82:361-369.)
© 2007 by Society for Leukocyte Biology

Modulation of NFAT-dependent gene expression by the RhoA signaling pathway in T cells

Whitney S. Helms*,{dagger},1, Jerry L. Jeffrey{dagger},{ddagger}, Derek A. Holmes*,{dagger}, Michael B. Townsend{dagger},2, Neil A. Clipstone§ and Lishan Su*,{dagger},{ddagger},3

* Department of Microbiology and Immunology,
{dagger} Lineberger Comprehensive Cancer Center, and
{ddagger} Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; and
§ Department of Pharmacology, Loyola University Medical School, Maywood, Illinois, USA

3 Correspondence: Lineberger Comprehensive Cancer Center, Room 22-056, CB#7295, Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599-7295, USA. E-mail: lsu{at}med.unc.edu

We have reported previously that p115Rho guanine nucleotide exchange factor, its upstream activator G{alpha}13, and its effector RhoA are able to inhibit HIV-1 replication. Here, we show that RhoA is able to inhibit HIV-1 gene expression through the NFAT-binding site in the HIV long-terminal repeat. Constitutively active NFAT counteracts the inhibitory activity of RhoA, and inhibition of NFAT activation also inhibits HIV-1 gene expression. We have shown further that RhoA inhibits NFAT-dependent transcription and IL-2 production in human T cells. RhoA does not inhibit nuclear localization of NFAT but rather, inhibits its transcriptional activity. In addition, RhoA decreases the level of acetylated histone H3, but not NFAT occupancy, at the IL-2 promoter. These data suggest that activation of RhoA can modulate IL-2 gene expression by inhibiting the transcriptional activity of NFAT and chromatin structure at the IL-2 promoter during T cell activation.

Key Words: GTPase • HIV-1 • IL-2




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