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.
Valdor
Rut
R
Transplant Unit, University Hospital Virgen de la Arrixaca, Ciberehd Murcia, Spain.
Schreiber
Valérie
V
Saenz
Luis
L
Martínez
Teresa
T
Muñoz-Suano
Alba
A
Dominguez-Villar
Margarita
M
Ramírez
Pablo
P
Parrilla
Pascual
P
Aguado
Enrique
E
García-Cózar
Francisco
F
Yélamos
José
J
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000328:Adult; D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D005434:Flow Cytometry; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D013379:Substrate Specificity / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
C468783:H2AX protein, human; D006657:Histones; D050778:NFATC Transcription Factors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011064:Poly Adenosine Diphosphate Ribose; D015759:Ionomycin; D011065:Poly(ADP-ribose) Polymerases; D013755:Tetradecanoylphorbol Acetate