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NF-AT activation requires suppression of Crm1-dependent export by calcineurin

Abstract

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 (15). 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 (68). 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 Crm1 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.

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Figure 1: Nuclear export signals and Crm1-binding sites in NF-AT4.
Figure 2: Calcineurin binding abolishes NF-AT4 nuclear export by Crm1.
Figure 3: Calcium regulates nuclear export by calcineurin.
Figure 4: Direct competition between calcineurin and Crm1.
Figure 5: NF-AT shuttling and transcriptional activity.

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Acknowledgements

We thank A. Yang and T. Rapoport for helpful discussions and comments on this manuscript, and G. Grosveld, R. Reed and B. Wolff for reagents used in this study. This work was supported by grants from the NIH and the American Cancer Society.

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Correspondence to Frank McKeon.

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Zhu, J., McKeon, F. NF-AT activation requires suppression of Crm1-dependent export by calcineurin. Nature 398, 256–260 (1999). https://doi.org/10.1038/18473

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