The T-cell transcription factor NFAT sub(p) is a substrate for calcineurin and interacts with Fos and Jun

• Published in: Nature (London) 1993-01, Vol.365 (6444), p.352-355
• Main Authors: Jain, J, McCaffrey, P G, Miner, Z, Kerppola, T K, Lambert, J N, Verdine, G L, Curran, T, Rao, A
• Format: Article
• Language: English
• ISSN: 0028-0836

Transcription of lymphokine genes in activated T cells is inhibited by the immunosuppressive agents cyclosporin A and FK506, which act by blocking the phosphatase activity of calcineurin. NFAT, a DNA-binding protein required for interleukin-2 gene transcription, is a potential target for calcineurin, cyclosporin A and FK506. NFAT contains a subunit (NFAT sub(p)) which is present in unstimulated T cells and which forms a complex with Fos and Jun proteins in the nucleus of activated T cells. Here we report that NFAT sub(p) is a DNA-binding phosphoprotein of relative molecular mass similar to 120,000 and is a substrate for calcineurin in vitro. Purified NFAT sub(p) forms DNA-protein complexes with recombinant Jun homodimers or Jun-Fos heterodimers; the DNA-binding domains of Fos and Jun are essential for the formation of the NFAT sub(p)-Fos-Jun-DNA complex. The interaction between the lymphoid-specific factor NFAT sub(p) and the ubiquitous transcription factors Fos and Jun provides a novel mechanism for combinatorial regulation of interleukin-2 gene transcription, which integrates the calcium-dependent and the protein-kinase C-dependent pathways of T-cell activation.