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NFAT5, Which Protects Against Hypertonicity, Is Activated by That Stress Via Structuring of Its Intrinsically Disordered Domain

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NFAT5, Which Protects Against Hypertonicity, Is Activated by That Stress Via Structuring of Its Intrinsically Disordered Domain NFAT5, which protects against hypertonicity, is activated by that stress via structuring of its intrinsically disordered domain Raj Kumara, Jenna F. DuMondb, Shagufta H. Khanc, E. Brad Thompsond,YiHee, Maurice B. Burgb,1, and Joan D. Ferrarisb aDepartment of Biomedical Sciences, College of Medicine, University of Houston, Houston, TX 77204; bSystems Biology Center, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD 20892; cDepartment of Medical Education, Geisinger Commonwealth School of Medicine, Scranton, PA 18509; dDepartment of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555; and eBiochemistry and Biophysics Center, Division of Intramural Research, National Heart, Lung and Blood Institute, Bethesda, MD 20892 Contributed by Maurice B. Burg, June 20, 2020 (sent for review July 19, 2019; reviewed by Prakash Kulkarni, S. Stoney Simons, Jr., and Vladimir N. Uversky) Nuclear Factor of Activated T cells 5 (NFAT5) is a transcription factor extracellular tonicity (13–15). NFAT5 is a multidomain transcrip- (TF) that mediates protection from adverse effects of hypertonicity tion factor (TF) in which the ID N-terminal domain (NTD) in- by increasing transcription of genes, including those that lead to cludes a tonicity-dependent auxiliary export region responsible for cellular accumulation of protective organic osmolytes. NFAT5 has nuclear and cytoplasmic localization and AD1 (amino acids 1–76), three intrinsically ordered (ID) activation domains (ADs). Using the one of NFAT5’s three activation domains (16–22). NFAT5 ID NFAT5 N-terminal domain (NTD), which contains AD1, as a model, C-terminal domain (CTD) contains two tonicity-dependent trans- we demonstrate by biophysical methods that the NTD senses osmo- activation domains, AD2 and AD3. Although AD1 alone is the lytes and hypertonicity, resulting in stabilization of its ID regions. In weakest of the three, its inclusion in test constructs doubles the the presence of sufficient NaCl or osmolytes, trehalose and sorbitol, hypertonicity response of AD2 or AD2AD3 (18, 19). the NFAT5 NTD undergoes a disorder-to-order shift, adopting higher ID regions are disproportionately higher in cell-signaling average secondary and tertiary structure. Thus, NFAT5 is activated by proteins, giving them an advantage over proteins with ordered the stress that it protects against. In its salt and/or osmolyte-induced conformations, since proteins with ID regions can more effi- PHYSIOLOGY more ordered conformation, the NTD interacts with several proteins, ciently and selectively interact with appropriate target binding including HMGI-C, which is known to protect against apoptosis. – These findings raise the possibility that the increased intracellular partner proteins and enhance allosteric responses (23 33). The ID ionic strength and elevated osmolytes caused by hypertonicity acti- regions of many TFs are known to undergo disorder-to-order vate and stabilize NFAT5. conformational transition upon interacting with organic osmo- lytes and encounters with specific target binding molecules (26, NFAT5 | hypertonicity | osmolytes | intrinsically disordered region | 27). Due to their lack of stable structure, the detailed mecha- protein–protein interactions nism behind the functions of NFAT5’s ID regions are unknown. We chose to investigate first the simpler of NFATs two major ammalian cells have adaptive responses that enhance sur- Mvival during various forms of stress (1). Among these, un- Significance compensated extracellular hyperosmotic stress results in osmotic outflow of water with a concomitant reduction in cell volume and NFAT5 mediates protection from adverse effects of hyperto- an increase in intracellular ionic strength. This leads to cell cycle nicity. Cells, e.g. kidney, in hypertonic conditions take up salts delay, DNA breakage, oxidative stress, and apoptotic death (2–4). and protective organic osmolytes. By mechanisms not fully Cells adapt to hypertonic stress by accumulating organic osmolytes, understood, NFAT5 is activated and induces genes including which are known to compensate for the cell volume reduction in- those that code enzymes responsible for synthesizing protec- duced by the hyperosmotic environment by allowing for the osmotic tive osmolytes. We show that in solution the NFAT5 NTD, influx of water into cells. Under isosmotic conditions, a reduction or which contains one of NFAT5′s three transcription activation loss of intracellular osmolytes mayalsoleadtoafunctionalre- domains, undergoes hypertonicity- and/or osmolyte-induced duction in cell volume and an increase in ionic strength sufficient to disorder-to-order conformational rearrangement. In its more compromise normal cellular metabolic and biochemical function folded conformation, interaction of NFAT5 NTD with specific (5–8). Another known function of such osmolytes is to protect proteins is enhanced, including that with high mobility group proteins from denaturation by preserving their native structure in protein (HMGI-C), which has been shown to protect against the face of potentially denaturing conditions. The possibility that apoptosis. These findings suggest that in vivo, increased in- this function may apply in hyperosmotic stress has, to our knowl- tracellular ionic strength, coupled with osmolytes, may directly edge, not been investigated, nor has the possibility that high salt activate NFAT5. They encourage further pursuit of this possibility. alone can stabilize any intrinsically ordered (ID) region of Nuclear Author contributions: R.K., J.F.D., E.B.T., Y.H., M.B.B., and J.D.F. designed research; R.K., Factor of Activated T cells 5 (NFAT5). J.F.D., S.H.K., and Y.H. performed research; R.K., J.F.D., S.H.K., E.B.T., Y.H., and J.D.F. The osmosensitive TF NFAT5/TonEBP/OREBP plays a cru- contributed new reagents/analytic tools; R.K., J.F.D., S.H.K., E.B.T., Y.H., M.B.B., and cial role protecting cells against deleterious effects of hyper- J.D.F. analyzed data; and R.K., J.F.D., E.B.T., Y.H., M.B.B., and J.D.F. wrote the paper. osmotic stress upon urinary concentration, the adaptive immune Reviewers: P.K., City of Hope National Medical Center; S.S.S., National Institutes of Health; response, and other physiological systems, particularly in tissues and V.N.U., University of South Florida. that experience large fluctuations in tonicity, such as the renal The authors declare no competing interest. medulla (9–12). NFAT5 modulates cellular response to osmotic Published under the PNAS license. changes by enhancing the expression of target genes, including 1To whom correspondence may be addressed. Email: [email protected]. those responsible for synthesis and/or transport of multiple organic This article contains supporting information online at https://www.pnas.org/lookup/suppl/ osmolytes, such that the intracellular concentration of compatible doi:10.1073/pnas.1911680117/-/DCSupplemental. protective osmolytes is increased and compensates for increased www.pnas.org/cgi/doi/10.1073/pnas.1911680117 PNAS Latest Articles | 1of6 Downloaded by guest on September 29, 2021 ID regions, hypothesizing that in the presence of appropriate Results concentrations of compatible osmolyte(s) or simple inorganic NFAT5 NTD Shows ID Characteristics. Secondary structural analysis salts, the ID NTD of NFAT5 would undergo disorder-to-order of the NFAT5 NTD (amino acids 2–220) predicted a large conformational rearrangements that would enhance protein–protein amount of sequence in random coil (ID) configuration (SI Ap- interactions. pendix, Supplementary Methods), with more than 75% of the In this study, we show our hypothesis to be correct: When NTD sequence random coil and only a small proportion as helix incubated with the natural organic osmolytes trehalose or sor- or sheet (SI Appendix, Fig. S1). We used several independent bitol, NFAT5 NTD changes from ID to more ordered conforma- predictors to analyze the ID nature of NFAT5 NTD. Analysis by tion, consistent with a two-state transition. In this folded conformation, IUPred showed ID regions in NFAT5 (SI Appendix, Fig. S2). We the interaction of NFAT5 NTD with specific proteins, e.g., high also applied ANCHOR, which predicts potential binding regions mobility group protein (HMGI-C), is significantly enhanced. within ID proteins. Such regions function by undergoing a We also found that ID NTD can adopt higher secondary/ter- disorder-to-order transition upon binding to a protein partner. tiary structure in the presence of NaCl. Sorbitol and NaCl are ANCHOR identifies segments in a generally disordered region known to work together to maintain cellular tonicity (6), and that cannot form enough favorable intrachain interactions to fold our data suggest that their structural effects are greater than the spontaneously and have the energetic capability to gain structure additive. These data show that NFAT5’sIDNTDcanbecome by interacting with a globular partner protein (SI Appendix, Fig. more structured in the presence of osmolytes and inorganic salt, S2). Analysis by three different versions of PONDR for ID pre- and that this enhances important protein–protein interactions. diction further strengthened the case for the ID nature of NFAT5 SI Appendix Such interactions are the natural function of TFs. These results NTD, evident from PONDR scores over 0.5 ( ,Fig. provide proof of principle of a physical basis for salt and S3). Further, computational analysis of ID predisposition of the osmolyte actions on NFAT5 structure and
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