NF-AT activation requires suppression of Crm1-dependent export by calcineurin.
Nuclear import of the NF-AT transcription factors during T-cell activation requires the calcium-activated phosphatase calcineurin, which unmasks nuclear-location signals on NF-AT. We show here that the nuclear import of NF-ATs is not sufficient to activate NF-AT target genes, as NF-ATs are subject to a futile cycling across the nuclear envelope owing to engagement with the exportin protein Crm1. Calcineurin suppresses this futile cycling by a non-catalytic mechanism involving the masking of nuclear export signals on NF-AT targeted by Crm1. This clustering of binding sites for calcineurin and Crml on NF-AT establishes an inherent competition between these molecules that imparts exquisite calcium sensitivity to the shuttling dynamics of the NF-AT transcription factors. Such a balance between nuclear import and export may regulate the action of other transcription factors.
Zhu
J
J
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
McKeon
F
F
D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D006822:Hybrid Cells; D028884:Karyopherins; D009154:Mutation; D050778:NFATC Transcription Factors; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D011233:Precipitin Tests; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000097606:Exportin 1 Protein
D019703:Calcineurin; D002118:Calcium; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D028884:Karyopherins; D050778:NFATC Transcription Factors; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000097606:Exportin 1 Protein