NFAt

NFAT, or Nuclear Factor of Activated T cells, is a family of transcription factors that regulate gene expression in response to intracellular calcium signaling. In mammals, the NFAT family includes NFAT1 (also called NFATc2), NFAT2 (NFATc1), NFAT3 (NFATc4), and NFAT4 (NFATc3), along with NFAT5 (TonEBP), the latter being regulated by osmoregulatory signals rather than calcineurin. NFAT proteins are cytoplasmic in resting cells when phosphorylated; upon calcium influx, the serine/threonine phosphatase calcineurin is activated and dephosphorylates NFAT, exposing a nuclear localization signal and enabling translocation to the nucleus where NFAT can influence transcription.

Within the nucleus, NFAT binds DNA at specific consensus sites and regulates target genes. Its activity often depends on interaction with AP-1 transcription factors (such as Fos and Jun), forming cooperative complexes that influence transcriptional outcomes. The regulatory balance of phosphorylation and dephosphorylation also controls NFAT’s nuclear export and long-term gene expression patterns.

NFAT plays a central role in immune responses, particularly T cell activation and differentiation. It controls cytokine gene expression, including IL-2, IL-4, IL-5, IL-13, and IFN-γ, and participates in shaping Th1/Th2 and other T cell fates. Beyond the immune system, NFAT signaling affects cardiac development and function, vascular biology, skeletal muscle, and neuronal processes. Dysregulation of NFAT activity has been linked to autoimmune diseases, chronic inflammation, and cancer.

Clinically, calcineurin inhibitors such as cyclosporine A and tacrolimus (FK506) block NFAT activation and are widely used as immunosuppressants in organ transplantation and some autoimmune conditions. Side effects reflect NFAT’s broad role across tissues.