Regulation of Transcription Factor NFAT by ADP-Ribosylation

Abstract

ADP-ribosylation is a reversible posttranslational modification mediated by poly-ADP-ribose polymerase (PARP). The results of recent studies demonstrate that ADP-ribosylation contributes to transcription regulation. Here, we report that transcription factor NFAT binds to and is ADP-ribosylated by PARP-1 in an activation-dependent manner. Mechanistically, ADP-ribosylation increases NFAT DNA binding. Functionally, NFAT-mediated interleukin-2 (IL-2) expression was reduced in T cells upon genetic ablation or pharmacological inhibition of PARP-1. Parp-1^−/− T cells also exhibit reduced expression of other NFAT-dependent cytokines, such as IL-4. Together, these results demonstrate that ADP-ribosylation mediated by PARP-1 provides a molecular switch to positively regulate NFAT-dependent cytokine gene transcription. These results also imply that, similar to the effect of calcineurin inhibition, PARP-1 inhibition may be beneficial in modulating immune functions.

ACKNOWLEDGMENTS

We thank members of our laboratories for their critical reading of the manuscript. We are grateful for the assistance from the Laboratory of Macromolecular Analysis and Proteomics (AECOM) on mass spectrometry analysis.

O.A.O. and N. S.-N. are trainees sponsored by NIH training grants 1F31-GM66607 and 5T32-GM07491, respectively. This research is supported, in part, by grants from the National Institutes of Health (C.-W.C. and F. M.), American Diabetes Association (C.-W.C.), and American Heart Association (C.-W.C.).