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Cited by 11Signaling Pathways in DiseaseProtein Structure and DynamicsGenomics and Chromatin Dynamics

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Direct ionic stress sensing and mitigation by the transcription factor NFAT5

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Khandwala, Chandni B., Sarkar, Parijat, Schmidt, H. Broder, Ma, Mengxiao, Pusapati, Ganesh V., Lamoliatte, Frederic, Kinnebrew, Maia, Patel, Bhaven B., Tillo, Desiree, Lebensohn, Andres M., Rohatgi, Rajat·2025·Science Advances
DOI 10.1126/sciadv.adu3194PMC PMC11838016

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Abstract

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.

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Metadata

Authors
Khandwala, C. B., Sarkar, P., Schmidt, H. B., Ma, M., Pusapati, G. V., Lamoliatte, F., Kinnebrew, M., Patel, B. B., Tillo, D., Lebensohn, A. M., & Rohatgi, R.
Affiliations
  • Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Stanford Medicine (US)
  • Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU), School of Life Sciences, University of Dundee, Dundee, UK.
  • National Institutes of Health (US)
Corresponding author
  • Sarkar, Parijat
  • Rohatgi, Rajat
ORCID
Venue
Science Advances
Publisher
American Association for the Advancement of Science (AAAS)
Published
2025-02-21
Volume
11
Issue
8
Pages
eadu3194-eadu3194
ISSN
2375-2548 (ISSN-L)
DOI
10.1126/sciadv.adu3194
PMC
PMC11838016
OpenAlex
W4407737904
Cited by
11
References
5
Citations by year
2026: 6 · 2025: 3
FWCI
2.71
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Science Advances (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
Funders
National Institute of General Medical Sciences (R35GM118082)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords
ionic stress, NFAT5, prion-like domains, BRD4, transcriptional coactivator, condensate, transcriptional regulation, Rel family transcription factors

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