Direct ionic stress sensing and mitigation by the transcription factor NFAT5.
Direct ionic stress sensing and mitigation by the transcription factor NFAT5.
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通过转录因子 NFAT5 直接感应和缓解离子应力。
DOI：
10.1101/2023.09.23.559074
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Rohatgi,Rajat
中科院分区：
文献类型：
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作者：
Khandwala,ChandniB;Sarkar,Parijat;Schmidt,HBroder;Ma,Mengxiao;Kinnebrew,Maia;Pusapati,GaneshV;Patel,BhavenB;Tillo,Desiree;Lebensohn,AndresM;Rohatgi,Rajat
由气候变化引起的温度升高和水资源短缺越来越多地使我们的细胞和组织暴露于离子应力，这是细胞质离子强度升高的结果，可以破坏蛋白质，细胞器和基因组功能。在这里，我们揭示了一个单一的蛋白质机制，离子强度传感和缓解动物细胞，一个是显着不同的类似的高渗透压甘油激酶级联在酵母中。Rel家族转录因子NFAT 5使用C末端朊病毒样结构域（PLD）直接感知细胞内离子强度。在响应升高的细胞内离子强度，这个PLD是必要的，足以通过招募转录辅激活因子BRD4来协调适应性基因表达程序。纯化的NFAT 5 PLD在体外响应于升高的溶液离子强度而形成缩合物，并且单独的人NFAT 5足以在酵母中重建哺乳动物对离子应激的转录响应。我们建议，离子敏感的构象变化在PLD直接调节转录，以维持离子强度的动物细胞内的稳态。
Rising temperatures and water scarcity caused by climate change are increasingly exposing our cells and tissues to ionic stress, a consequence of elevated cytoplasmic ionic strength that can disrupt protein, organelle, and genome function. Here, we unveil a single-protein mechanism for ionic strength sensing and mitigation in animal cells, one that is notably different from the analogous high osmolarity glycerol kinase cascade in yeast. The Rel family transcription factor NFAT5 directly senses intracellular ionic strength using a C-terminal prion-like domain (PLD). In response to elevated intracellular ionic strength, this PLD is necessary and sufficient to coordinate an adaptive gene expression program by recruiting the transcriptional coactivator BRD4. The purified NFAT5 PLD forms condensates in response to elevated solution ionic strength in vitro, and human NFAT5 alone is sufficient to reconstitute a mammalian transcriptional response to ionic stress in yeast. We propose that ion-sensitive conformational changes in a PLD directly regulate transcription to maintain ionic strength homeostasis in animal cells.