Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A

Abstract

CYCLOSPORINA and FK506 inhibit T- and B-cell activation and other processes essential to an effective immune response1–3. In T lymphocytes these drugs disrupt an unknown step in the trans-mission of signals from the T-cell antigen receptor to cytokine genes that coordinate the immune response4–6. The putative intracellular receptors for FK506 and cyclosporin arecis-trans prolyl isomerases7–11. Binding of the drug inhibits isomerase activity8,10,11, but studies with other prolyl isomerase inhibitors12 and analysis of cyclosporin-resistant mutants in yeast suggest that the effects of the drug result from the formation of an inhibitory complex between the drug and isomerase13,14, and not from inhibi-tion of isomerase activity. A transcription factor, NF-AT, which is essential for early T-cell gene activation, seems to be a specific target of cyclosporin A and FK506 action because transcription directed by this protein is blocked in T cells treated with these drugs, with little or no effect on other transcription factors such as AP-1 and NF-κB (refs 15–17). Here we demonstrate that NF-AT is formed when a signal from the antigen receptor induces a pre-existing cytoplasmic subunit to translocate to the nucleus and combine with a newly synthesized nuclear subunit of NF-AT. FK506 and cyclosporin A block translocation of the cytoplasmic component without affecting synthesis of the nuclear subunit.

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Flanagan, W., Corthésy, B., Bram, R. et al. Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A. Nature 352, 803–807 (1991). https://doi.org/10.1038/352803a0

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