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Molecular and Cellular Biology, May 2008, p. 2860-2871, Vol. 28, No. 9
0270-7306/08/$08.00+0     doi:10.1128/MCB.01746-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Regulation of Transcription Factor NFAT by ADP-Ribosylation{triangledown}

Opeyemi A. Olabisi,1 Noemi Soto-Nieves,2 Edward Nieves,3 Teddy T. C. Yang,1 XiaoYong Yang,1 Raymond Y. L. Yu,1 Hee Yun Suk,1 Fernando Macian,2 and Chi-Wing Chow1*

Department of Molecular Pharmacology,1 Department of Pathology,2 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 104613

Received 24 September 2007/ Returned for modification 2 November 2007/ Accepted 15 February 2008

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.

* Corresponding author. Mailing address: Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-2716. Fax: (718) 430-8922. E-mail: cchow{at}aecom.yu.edu

{triangledown} Published ahead of print on 25 February 2008.

Molecular and Cellular Biology, May 2008, p. 2860-2871, Vol. 28, No. 9
0270-7306/08/$08.00+0     doi:10.1128/MCB.01746-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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