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首页> 外文期刊>Current Biology: CB >Dynamic Assembly of a Membrane Signaling Complex Enables Selective Activation of NFAT by Orai1
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Dynamic Assembly of a Membrane Signaling Complex Enables Selective Activation of NFAT by Orai1

机译：膜信号复合物的动态组装使Orai1选择性激活NFAT。

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NFAT-dependent gene expression is essential for the development and function of the nervous, immune, and cardiovascular systems and kidney, bone, and skeletal muscle [1]. Most NFAT protein resides in the cytoplasm because of extensive phosphorylation, which masks a nuclear localization sequence. Dephosphorylation by the Ca2+-calmodulin-activated protein phosphatase calcineurin triggers NFAT migration into the nucleus [2, 3]. In some cell types, NFAT can be activated by Ca2+ nanodomains near open store-operated Orai1 and voltage-gated Ca2+ channels in the plasma membrane [4, 5]. How local Ca2+ near Orai1 is detected and whether other Orai channels utilize a similar mechanism remain unclear. Here, we report that the paralog Orai3 fails to activate NFAT. Orai1 is effective in activating gene expression via Ca2+ nanodomains because it participates in a membrane-delimited signaling complex that forms after store depletion and brings calcineurin, via the scaffolding protein AKAP79, to calmodulin tethered to rail. By contrast, Orai3 interacts less well with AKAP79 after store depletion, rendering it ineffective in activating NFAT. A channel chimera of Orai3 with the N terminus of rail was able to couple local Ca2+ entry to NFAT activation, identifying the N-terminal domain of Orai1 as central to Ca2+ nanodomain-transcription coupling. The formation of a store-dependent signaling complex at the plasma membrane provides for selective activation of a fundamental downstream response by rail.
机译：NFAT依赖的基因表达对于神经，免疫和心血管系统以及肾脏，骨骼和骨骼肌的发育和功能至关重要[1]。大多数NFAT蛋白由于广泛的磷酸化而驻留在细胞质中，从而掩盖了核定位序列。 Ca2 +-钙调蛋白激活的蛋白磷酸酶钙调磷酸酶的去磷酸化触发NFAT迁移到细胞核中[2，3]。在某些细胞类型中，NFAT可以被质膜中开放存储操作的Orai1和电压门控的Ca2 +通道附近的Ca2 +纳米域激活[4，5]。目前尚不清楚如何检测Orai1附近的局部Ca2 +以及其他Orai通道是否利用类似的机制。在这里，我们报告，旁系同源Orai3无法激活NFAT。 Orai1可有效地通过Ca2 +纳米域激活基因表达，因为它参与了膜限定的信号复合物，该信号复合物在存储耗尽后形成，并通过支架蛋白AKAP79将钙调神经磷酸酶束缚在钙调蛋白上。相比之下，存储耗尽后，Orai3与AKAP79的交互作用较差，使其无法激活NFAT。 Orai3的通道嵌合体与N轨的末端能够将局部Ca2 +进入偶联至NFAT激活，从而将Orai1的N末端域识别为Ca2 +纳米域-转录偶联的中心。在质膜上的依赖于存储的信号复合物的形成提供了通过轨道选择性激活基本下游反应的能力。

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