NFATc

Nuclear factor of activated T cells cytosolic NFATc... 

Nuclear Factor of Activated T Cells Cytosolic NFATc... 

Fig. 4.1 Mechanism of action of cyclosporine. Cyclosporine readily diffuses into the cytoplasm of the target cells where it binds to cyclophilins. The cyclosporine-cyclophilin complex stably associates with calcineurin and inhibits calcineurin activity. Calcineurin is a Ca2+-dependent enzyme— serine/threonine phosphatase— which after activation by Ca2+, dephosphorylates a cytosolic component of NFAT (NFATc, cytosolic factor of activated T cells). After dephosphorylation, NFATc migrates from the cytoplasm to the nucleus where it associates with NFATn and induces transcription of several cytokine genes including IL-2. Cyclosporine inhibits calcineurin activity after associating with cyclophilins, resulting in the inhibition of IL-2 production and other cytokines (see Color Insert)...

NFATc, and as a result, the transport of NFATc to the nucleus is prevented and consequently its association with NFATn does not proceed (Fig. 4.1). The association of NFATc with NFATn is essential for the initiation of IL-2 production, which is achieved through binding of NFATc-NFATn to the promoter of the IL-2 gene. As a result, IL-2 production is inhibited, which is necessary for the optimal function of the immune response. Cyclosporine does not inhibit cytokine-induced transduction mechanisms and also has no effect on antigen recognition by T cells in the context of MHC molecules. 

Tacrolimus suppresses peptidyl-prolyl isomerase activity by binding to the immuno-philin FK506-binding protein-12 (FKBP-12), and the tacrolimus-FKBP-12 complex binds to calcineurin and inhibits calcineurin phosphatase activity. As a result, calcineurin is unable to dephosphorylate NFATc and thus its migration to nucleus is blocked where its association with NFATn is necessary for the activation of key cytokine genes. Therefore, its mechanism of action is similar to cyclosporine although tacrolimus binds to a separate set of immunophilins in the cytoplasm. Tacrolimus, like cyclosporine, inhibits the secretion of key cytokines and inhibits T-cell activation (Fig. 4.2). 

As a result of dephosphorylation, NFATc moves from the cytoplasm to the nucleus... 

NFATc associates with other nuclear components... 

S. A. Wolfe, et al. Unusual Rel-like architecture in the DNA-binding domain of the transcription factor NFATc. Nature, 38S, 172-176, 1997. 

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