Direct ionic stress sensing and mitigation by the transcription factor NFAT5

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.