Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 28, Issue 9, Pages 2860-2871Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.01746-07
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Funding
- NCRR NIH HHS [S10 RR019352] Funding Source: Medline
- NIAID NIH HHS [R01 AI059738, R01 AI059738-04] Funding Source: Medline
- NIDDK NIH HHS [R01 DK063167-05, R01 DK063167, R01 DK063167-03, R01 DK063167-02, R01 DK063167-04, R01 DK063167-01A2] Funding Source: Medline
- NIGMS NIH HHS [F31 GM066607, 1F31-GM66607, 5T32-GM07491, T32 GM007491] Funding Source: Medline
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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.
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