Regulation of NFAT by poly(ADP-ribose) polymerase activity in T cells.

The nuclear factor of activated T cells (NFAT) family of transcription factors is pivotal for T lymphocyte functionality. All relevant NFAT activation events upon T cells stimulation such as nuclear translocation, DNA binding, and transcriptional activity have been shown to be dictated by its phosphorylation state. Here, we provide evidence ...
for a novel post-translational modification that regulates NFAT. Indeed, NFATc1 and NFATc2 are poly(ADP-ribosyl)ated by poly-ADP-ribose polymerase-1 (PARP-1). Moreover, we have also found a physical interaction between PARP-1 and both NFATc1 and NFATc2. Interestingly, PARP is activated during T cell stimulation in the absence of DNA damage, leading to ADP-ribose polymers formation and transfer to nuclear acceptor proteins. Our data suggest that poly(ADP-ribosyl)ation modulates the activation of NFAT in T cells, as PARP inhibition causes an increase in NFAT-dependent transactivation and a delay in NFAT nuclear export. Poly(ADP-ribosyl)ation will expedited NFAT export from the nucleus directly or by priming/facilitating NFAT phosphorylation. Altogether, these data point to PARP-1 and poly(ADP-ribosyl)ation as a novel regulatory mechanism of NFAT at nuclear level, suggesting a potential use of PARP as a new therapeutic target in the modulation of NFAT.
Mesh Terms:
Active Transport, Cell Nucleus, Adult, Animals, Cell Nucleus, Enzyme Induction, Flow Cytometry, Hela Cells, Histones, Humans, Ionomycin, Jurkat Cells, Lymphocyte Activation, Mice, NFATC Transcription Factors, Phosphorylation, Poly Adenosine Diphosphate Ribose, Poly(ADP-ribose) Polymerases, Protein Binding, Substrate Specificity, T-Lymphocytes, Tetradecanoylphorbol Acetate, Transcriptional Activation
Mol. Immunol.
Date: Apr. 01, 2008
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