Sodium ion regulates liquidity of biomolecular condensates in hyperosmotic stress response

Abstract

SummaryBiomolecular condensates are membraneless structures formed through phase separation. Recent studies have demonstrated that the material properties of biomolecular condensates are crucial for their biological functions and pathogenicity. However, the phase maintenance of biomolecular condensates in cells remains elusive. Here, we show that sodium ion (Na+) influx regulates the condensate liquidity under hyperosmotic stress. The fluidity of ASK3 condensates increases at the high intracellular Na+ concentration derived from extracellular hyperosmotic solution. Moreover, we identified TRPM4 as a cation channel that allows Na+ influx under hyperosmotic stress. TRPM4 inhibition causes the liquid-to-solid phase transition of ASK3 condensates, leading to impairment of the ASK3 osmoresponse. In addition to ASK3 condensates, intracellular Na+ widely regulates the condensate liquidity and aggregate formation of biomolecules, including DCP1A, TAZ and polyQ-protein, under hyperosmotic stress. Our findings demonstrate that changes in Na+ contribute to the cellular stress response via liquidity maintenance of biomolecular condensates.

Direct ionic stress sensing and mitigation by the transcription factor NFAT5

“…We considered whether the response of NFAT5 to ionic stress was shared with other IDR-containing proteins since increased intracellular sodium has been shown to increase the liquidity of ASK3 condensates. 67 Hypertonic and ionic stress did not alter the condensation behavior of IDRs from nine other transcriptional regulators that undergo PSCP in various contexts, suggesting that this is a property unique to NFAT5 ( Figure S5A ). 68,69 Ionic stress sensitivity also seems to be an evolutionarily conserved property of the NFAT5 proteins, since it was retained when the CTD of human NFAT5 was replaced with that from bird, fish, amphibian and even invertebrate NFAT5 homologs ( Figure S5B ).…”

“…Future studies will investigate how cellular responses to ionic stress are different from previously-described responses to hypertonic stress. Interestingly, intracellular sodium can regulate the material properties of the cell volume regulatory kinase ASK3 67 , suggesting a wider set of ionic strength sensitive pathways. Permeable salts (analogous to NH 4 OAc used in this study) provide a simple and powerful way to impose ionic stress on cells without causing cell shrinkage, water loss and increased macromolecular crowding.…”

TSC22D,WNKandNRBPgene families exhibit functional buffering and evolved with Metazoa for macromolecular crowd sensing

“…Fifth, we did not detect ASK3(MAP3K15) as a genetic or physical interaction in our study, despite detectable mRNA levels for MAP3K15. ASK3 was previously reported to phase separate and to bind and suppress WNK1 and SPAK/OSR1 function in the kidney [77][78][79] . WNK1, NRBP1, OSR1, and phosphorylated OSR1 S325 /SPAK S373 .…”

Sodium as an Important Regulator of Immunometabolism

“…Interestingly, sodium was recently also identified as a regulator of the liquidity of intracellular condensates, affecting protein-protein interactions (at least partially by electrostatic shielding of the proteins) and thus protein aggregation under hypertonic stress. 99 However, the exact extend of salt-induced metabolic remodeling in various different cell types remains ill defined. And there are so far only limited data available in respect to time resolution of salt-induced metabolic remodeling in different cell types under different metabolic states.…”