Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca(2+) Signals.
Control of NFAT Isoform Activation and NFAT-Dependent Gene Expression through Two Coincident and Spatially Segregated Intracellular Ca(2+) Signals.
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DOI：
10.1016/j.molcel.2016.11.011
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发表时间：
2016-11-17
期刊：
影响因子：
16
通讯作者：
Parekh, Anant B.
中科院分区：
文献类型：
--
作者：
Kar, Pulak;Mirams, Gary R.;Christian, Helen C.;Parekh, Anant B.
兴奋-转录偶联，将细胞表面的刺激与核基因表达的变化联系起来，在整个真核生物中是保守的。如何密切相关的共表达转录因子的差异激活仍然不清楚。在这里，我们表明，两个钙离子依赖性转录因子亚型，NFAT 1和NFAT 4，需要不同的亚细胞InsP 3和Ca 2+信号生理持续激活。NFAT 1受质膜下Ca 2+微结构域刺激，而NFAT 4另外需要通过核InsP 3受体从内核被膜动员Ca 2+。在细胞质和细胞核中，NFAT 1的再磷酸化（失活）比NFAT 4更慢，从而使激活期更长。细胞质Ca 2+的振荡，长期以来被认为是Ca 2+信号传导的生理形式，在激活NFAT蛋白中没有作用。相反，NFAT 4的有效持续生理激活与核Ca 2+的振荡紧密相关。我们的研究结果表明，基因表达可以控制一致的但地理上不同的Ca 2+信号，由一个自由扩散的InsP 3消息。NFAT 1通过局部Ca 2+进入激活，而NFAT 4也需要核Ca 2+通过位于内核膜上的InsP 3受体核Ca 2+增加NFAT 1和NFAT 4显示非常不同的再磷酸化（失活）动力学NFAT 1的缓慢失活提供了一种形式的基因表达的短期记忆NFAT 1和NFAT 4是广泛共表达的转录因子。NFAT 1被CRAC通道附近的Ca 2+微区激活，而NFAT 4另外需要核Ca 2+。Kar等人现在表明，核Ca 2+是由内核膜上的InsP 3受体升高的。NFAT异构体对不同亚细胞Ca 2+信号的依赖性调节细胞和刺激特异性环境中的基因表达。
Excitation-transcription coupling, linking stimulation at the cell surface to changes in nuclear gene expression, is conserved throughout eukaryotes. How closely related coexpressed transcription factors are differentially activated remains unclear. Here, we show that two Ca2+-dependent transcription factor isoforms, NFAT1 and NFAT4, require distinct sub-cellular InsP3 and Ca2+ signals for physiologically sustained activation. NFAT1 is stimulated by sub-plasmalemmal Ca2+ microdomains, whereas NFAT4 additionally requires Ca2+ mobilization from the inner nuclear envelope by nuclear InsP3 receptors. NFAT1 is rephosphorylated (deactivated) more slowly than NFAT4 in both cytoplasm and nucleus, enabling a more prolonged activation phase. Oscillations in cytoplasmic Ca2+, long considered the physiological form of Ca2+ signaling, play no role in activating either NFAT protein. Instead, effective sustained physiological activation of NFAT4 is tightly linked to oscillations in nuclear Ca2+. Our results show how gene expression can be controlled by coincident yet geographically distinct Ca2+ signals, generated by a freely diffusible InsP3 message. NFAT1 is activated by local Ca2+ entry, whereas NFAT4 also needs nuclear Ca2+ Nuclear Ca2+ increases via InsP3 receptors located on the inner nuclear membrane NFAT1 and NFAT4 show very different rephosphorylation (deactivation) kinetics Slow deactivation of NFAT1 affords a form of short-term memory to gene expression NFAT1 and NFAT4 are widely coexpressed transcription factors. NFAT1 is activated by Ca2+ microdomains near CRAC channels, whereas NFAT4 additionally requires nuclear Ca2+. Kar et al. now show that nuclear Ca2+ is raised by InsP3 receptors on the inner nuclear membrane. The dependence of NFAT isoforms on distinct sub-cellular Ca2+ signals regulates gene expression in cell- and stimulus-specific contexts.
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