Distinct spatial Ca2+ signatures selectively activate different NFAT transcription factor isoforms.
Distinct spatial Ca2+ signatures selectively activate different NFAT transcription factor isoforms.
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DOI：
10.1016/j.molcel.2015.02.027
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发表时间：
2015-04-16
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;Parekh, Anant B.
蛋白质亚型在生物系统中广泛表达。共存于同一亚细胞结构域内的亚型如何被差异激活仍不清楚。在这里，我们比较了两种密切相关的转录因子亚型 NFAT1 和 NFAT4 的调节机制，随着细胞内 Ca2+ 的增加（伴随着钙池操纵的 Orai1/CRAC 通道的开放），它们从细胞质迁移到细胞核。我们证明 NFAT1 与 Orai1 有一条专用的通信线路，可响应开放通道附近的 Ca2+ 微域而激活。相比之下，NFAT4 刺激需要局部 Ca2+ 进入和细胞核 Ca2+ 上升。我们将核位置的差异映射到 NFAT 调节域 SP-3 基序内的氨基酸。随着刺激强度的增加，不同的 Ca2+ 依赖性使激动剂能够招募不同的亚型组合。我们的研究揭示了一种机制，即共存的细胞质转录因子亚型被不同的亚细胞 Ca2+ 信号差异激活。细胞质 Ca2+ 激活 NFAT1 和 NFAT4 转录因子 NFAT1 受到质膜附近 Ca2+ 微域的刺激 Ca2+ 通道 NFAT4 需要 Ca2+ 微域和核 Ca2+ 上升 不同的 Ca2+ 依赖性赋予不同的 NFAT 核驻留时间 蛋白质亚型通常在细胞中共表达，占据相同的空间域，并被相同的细胞内信号激活。一种异构体的选择性招募是如何发生的尚不清楚。在这里，我们比较了 NFAT1 和 NFAT4 这两个密切相关的脊椎动物转录因子的激活。我们报告说，不同的亚型是由不同的亚细胞 Ca2+ 特征刺激的。 NFAT1 与质膜 Ca2+ 通道有一条专用的通讯线路，而 NFAT4 还需要细胞核 Ca2+ 上升。
Protein isoforms are widely expressed in biological systems. How isoforms that co-exist within the same sub-cellular domain are differentially activated remains unclear. Here, we compare the regulatory mechanism of two closely related transcription factor isoforms, NFAT1 and NFAT4, that migrate from the cytoplasm to the nucleus following the increase in intracellular Ca2+ that accompanies the opening of store-operated Orai1/CRAC channels. We demonstrate that NFAT1 has a private line of communication with Orai1, activating in response to Ca2+ microdomains near the open channels. By contrast, NFAT4 stimulation requires both local Ca2+ entry and a nuclear Ca2+ rise. We mapped differences in nuclear location to amino acids within the SP-3 motif of the NFAT regulatory domain. The different Ca2+ dependencies enable agonists to recruit different isoform combinations as stimulus strength increases. Our study uncovers a mechanism whereby co-existing cytoplasmic transcription factor isoforms are differentially activated by distinct sub-cellular Ca2+ signals. Cytoplasmic Ca2+ activates NFAT1 and NFAT4 transcription factors NFAT1 is stimulated by Ca2+ microdomains near plasma membrane Ca2+ channels NFAT4 requires both Ca2+ microdomains and a nuclear Ca2+ rise Different Ca2+ dependencies impart distinct NFAT nuclear residency times Protein isoforms are often co-expressed in cells, occupy the same spatial domain, and are activated by the same intracellular signal. How selective recruitment of one isoform occurs is unclear. Here, we have compared the activation of NFAT1 and NFAT4, two closely related vertebrate transcription factors. We report that the different isoforms are stimulated by distinct sub-cellular Ca2+ signatures. NFAT1 has a private line of communication with plasma membrane Ca2+ channels, whereas NFAT4 additionally requires a nuclear Ca2+ rise.
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影响因子：
9.2
作者：
Kar, Pulak;Nelson, Charmaine;Parekh, Anant B.
通讯作者：
Parekh, Anant B.
DOI：
10.1073/pnas.1201204109
发表时间：
2012-05-01
影响因子：
11.1
作者：
Kar, Pulak;Bakowski, Daniel;Parekh, Anant B.
通讯作者：
Parekh, Anant B.
影响因子：
4.8
作者：
Chang, Wei-Chiao;Nelson, Charmaine;Parekh, Anant B.
通讯作者：
Parekh, Anant B.
影响因子：
64.8
作者：
Prakriya, Murali;Feske, Stefan;Hogan, Patrick G.
通讯作者：
Hogan, Patrick G.
影响因子：
9.2
作者：
Di Capite, Joseph;Ng, Siaw Wei;Parekh, Anant B.
通讯作者：
Parekh, Anant B.