NF-AT

NF -AT or NFAT ( nuclear factor of activated T- cells) are transcription factors in T lymphocytes of vertebrates that bind with activation of a promoter in the nucleus and restart it as the gene expression of cytokines such as interleukin -2 ( IL -2). NF-AT have different characteristic binding sites: a DNA binding domain of the transcription as well as two different calcineurin binding domains for activation by calcineurin.

In humans is the protein NF- ATC1 (NF- AT2 ) NF- ATC2 (NF- AT1), NF- ATC3 (NF -AT4 ), NF- ATC4 (NF- AT3 ) and NF- AT5. NF- ATCX are cytosolic, while NF- AT5 is exclusively localized in the nucleus. NF- ATCX form in the nucleus together form a complex ( NFATc ), which is necessary for the transcription function. However, the subunits have also isolated functions.

Activation

The NF -AT are phosphorylated in the cytosol before. In this condition, they are inactive.

After activation of the T cell receptor of a T lymphocyte, it leads to a signaling cascade. The calcium concentration in the cytosol increases. These calcium ions together with calmodulin a complex binds calcineurin ( a phosphatase ). Characterized the catalytic subunit of calcineurin is activated. Calcineurin dephosphorylated the phosphorylated present nuclear localization signal of NF -AT. As a result of the NF-AT to be transported through the nuclear pore to the nucleus where they form the first complex of NFATc. This binds to NF-AT elements, binding sites specific for individual NF-AT to the DNA and thus activates the transcription of, for example, IL-2.

Following the IL- 2 gene expression of IL-2 binds to a autocrine IL -2 receptor of the T lymphocytes. Wherein the T lymphocyte is activated and induced to proliferate.

Inhibition

An inhibition of NF-AT is the one hand by an inhibition of calcineurin or calmodulin, which ensures the activation is prevented, or by a series of relatively small, usually bi-or tricyclic organic compounds which inhibit the binding of calcineurin of NF -AT. Clinical interest has the high immunosuppressive effect of the inhibition of NF-AT by cyclosporine A and tacrolimus ( FK 506), which are employed in organ transplants. Both immunosuppressive drugs block the activation of calcineurin.

de