|MoBio||NFAT, Calcineurin and Immunosuppression||Chapter 5|
Organ transplantation often elicits immune responses to reject the foreign object. The most widely used drugs to deal with such graft reaction are FK506 and cyclosporin A (CsA). Their direct target is a phosphatase known as calcineurin. CsA combines with a cellular protein called cyclophilin to inhibit calcineurin; FK506 combines with FKBP (FK506 binding protein) to inhibit the phosphatase.
How can inhibition of a phosphatase suppress the immune response? The answer lies in the transport of NFAT (nuclear factor of activated T cells) which is a transcription factor regulating IL-2.
NFAT contains both nuclear localization sequence (NLS) and nuclear export sequence (NES), but one of them is buried in the protein interior, inaccessible to importin and exportin. Whether NLS or NES is masked depends on the phosphorylation state of specific serine residues in the regulatory domain. Phosphorylation of these serine residues exposes NES whereas dephosphorylation exposes NLS.
In resting cells, the NLS of the cytoplasmic NFAT is masked due to phosphorylation on these serine residues. In stimulated cells, an increase of intracellular calcium ions activates calcineurin, which then dephosphorylates the masking residues. Consequently, NLS is exposed and NFAT can be carried into the nucleus by the importin α/β. Inside the nucleus, NFAT may be re-phosphorylated by protein kinase, exposing its NES and be exported by the exportin Crm1.