Nuclear localization of NF-ATc by a calcineurin-dependent, cyclosporin-sensitive intramolecular interaction

The NF-AT family of transcription factors participates in the regulation of early immune response genes such as IL-2, IL-4, CD40 ligand, and Fas ligand in response to Ca2+/calcineurin signals initiated at the antigen receptor. Calcineurin activation leads to the rapid translocation of NF-AT family m...

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Bibliographic Details
Published in:Genes & development 1997-04, Vol.11 (7), p.824-834
Main Authors: Beals, C R, Clipstone, N A, Ho, S N, Crabtree, G R
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Biological Transport - drug effects
Calcineurin
Calcium - metabolism
Calmodulin-Binding Proteins - metabolism
Cell Compartmentation - drug effects
Cell Nucleus
COS Cells
Cyclosporine - pharmacology
Cytoplasm
DNA-Binding Proteins - metabolism
Immunosuppressive Agents - pharmacology
Molecular Sequence Data
NFATC Transcription Factors
Nuclear Proteins - metabolism
Phosphoprotein Phosphatases - metabolism
Phosphorylation
Phosphoserine - metabolism
Recombinant Proteins - metabolism
Sequence Homology, Amino Acid
Serine - genetics
Serine - metabolism
Structure-Activity Relationship
Tacrolimus - pharmacology
Transcription Factors - metabolism
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Summary:The NF-AT family of transcription factors participates in the regulation of early immune response genes such as IL-2, IL-4, CD40 ligand, and Fas ligand in response to Ca2+/calcineurin signals initiated at the antigen receptor. Calcineurin activation leads to the rapid translocation of NF-AT family members from cytoplasm to nucleus, an event that is blocked by the immunosuppressive drugs cyclosporin A and FK506. We show that translocation requires two redundant nuclear localization sequences and that one sequence is in an intramolecular association with phosphorserines in a conserved motif located at the amino terminus of each NF-AT protein. Mutation of serines in this motif in NF-ATc both disrupts this intramolecular interaction and leads to nuclear localization, suggesting a model of NF-AT nuclear import in which dephosphorylation by calcineurin causes exposure of two nuclear localization sequences.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.11.7.824