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PreprintCited 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, Kinnebrew, Maia, Pusapati, Ganesh V., Patel, Bhaven B., Tillo, Desiree, Lebensohn, Andres M., Rohatgi, Rajat·2023·Science Advances
DOI 10.1101/2023.09.23.559074PMC PMC11838016

Preprint — published as 10.1126/sciadv.adu3194 · Paper page

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Abstract

SUMMARY: Homeostatic control of intracellular ionic strength is essential for protein, organelle and genome function, yet mechanisms that sense and enable adaptation to ionic stress remain poorly understood in animals. We find that the transcription factor NFAT5 directly senses solution ionic strength using a C-terminal intrinsically disordered region. Both in intact cells and in a purified system, NFAT5 forms dynamic, reversible biomolecular condensates in response to increasing ionic strength. This self-associative property, conserved from insects to mammals, allows NFAT5 to accumulate in the nucleus and activate genes that restore cellular ion content. Mutations that reduce condensation or those that promote aggregation both reduce NFAT5 activity, highlighting the importance of optimally tuned associative interactions. Remarkably, human NFAT5 alone is sufficient to reconstitute a mammalian transcriptional response to ionic or hypertonic stress in yeast. Thus NFAT5 is both the sensor and effector of a cell-autonomous ionic stress response pathway in animal cells.

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Metadata

Authors
Khandwala, C. B., Sarkar, P., Schmidt, H. B., Ma, M., Kinnebrew, M., Pusapati, G. V., Patel, B. B., Tillo, D., Lebensohn, A. M., & Rohatgi, R.
Affiliations
  • Stanford Medicine (US)
  • National Institutes of Health (US)
Corresponding author
  • Sarkar, Parijat
  • Rohatgi, Rajat
ORCID
Venue
Science Advances
Publisher
openRxiv
Published
2023-09-24
Volume
11
Issue
8
Pages
eadu3194-eadu3194
ISSN
2375-2548 (ISSN-L)
DOI
10.1101/2023.09.23.559074
PMC
PMC11838016
OpenAlex
W4407737904
Cited by
11
References
1
Citations by year
2026: 6 · 2025: 3 · 2024: 2
FWCI
2.67
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 Institutes of Health (1s10od012276-01)
  • 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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