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 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.
Beals
C R
CR
Department of Developmental Biology, Stanford University, California 94305-5428, USA.
Clipstone
N A
NA
Ho
S N
SN
Crabtree
G R
GR
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D019556:COS Cells; D019703:Calcineurin; D002118:Calcium / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000378:metabolism*; D002451:Cell Compartmentation / Q000187:drug effects*; D002467:Cell Nucleus; D016572:Cyclosporine / Q000494:pharmacology*; D003593:Cytoplasm; D004268:DNA-Binding Proteins / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*
D002148:Calmodulin-Binding Proteins; D004268:DNA-Binding Proteins; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D010768:Phosphoserine; D012694:Serine; D016572:Cyclosporine; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D002118:Calcium; D016559:Tacrolimus