Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The evolving role of TonEBP as an immunometabolic stress protein

Abstract

Tonicity-responsive enhancer-binding protein (TonEBP), which is also known as nuclear factor of activated T cells 5 (NFAT5), was discovered 20 years ago as a transcriptional regulator of the cellular response to hypertonic (hyperosmotic salinity) stress in the renal medulla. Numerous studies since then have revealed that TonEBP is a pleiotropic stress protein that is involved in a range of immunometabolic diseases. Some of the single-nucleotide polymorphisms (SNPs) in TONEBP introns are cis-expression quantitative trait loci that affect TONEBP transcription. These SNPs are associated with increased risk of type 2 diabetes mellitus, diabetic nephropathy, inflammation, high blood pressure and abnormal plasma osmolality, indicating that variation in TONEBP expression might contribute to these phenotypes. In addition, functional studies have shown that TonEBP is involved in the pathogenesis of rheumatoid arthritis, atherosclerosis, diabetic nephropathy, acute kidney injury, hyperlipidaemia and insulin resistance, autoimmune diseases (including type 1 diabetes mellitus and multiple sclerosis), salt-sensitive hypertension and hepatocellular carcinoma. These pathological activities of TonEBP are in contrast to the protective actions of TonEBP in response to hypertonicity, bacterial infection and DNA damage induced by genotoxins. An emerging theme is that TonEBP is a stress protein that mediates the cellular response to a range of pathological insults, including excess caloric intake, inflammation and oxidative stress.

Key points

  • Tonicity-responsive enhancer-binding protein (TonEBP) is a stress protein involved in the cellular response to hypertonicity, autoimmune reactions, inflammation and metabolic and genotoxic stress.

  • TonEBP-mediated responses to autoimmunity, viral infection and metabolic stresses are pathological.

  • TonEBP dysfunction is implicated in metabolic diseases, such as atherosclerosis, rheumatoid arthritis, obesity and type 2 diabetes mellitus.

  • TonEBP-mediated responses to hypertonicity, bacterial infection and genotoxins are protective.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Structural features of transcription factors and domain organization of TonEBP.
Fig. 2: Hypertonicity signalling to TonEBP.
Fig. 3: Non-hypertonic signalling to TonEBP.
Fig. 4: Homeostatic or protective functions of TonEBP associated with transcription regulation.
Fig. 5: Protective functions of TonEBP independent of transcription regulation.
Fig. 6: Molecular actions of TonEBP in response to pathological stresses.

References

  1. 1.

    Sheen, M. R. et al. Interstitial tonicity controls TonEBP expression in the renal medulla. Kidney Int. 75, 518–525 (2009).

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Kwon, M. S., Lim, S. W. & Kwon, H. M. Hypertonic stress in the kidney: a necessary evil. Physiology 24, 186–191 (2009).

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Miyakawa, H., Woo, S. K., Dahl, S. C., Handler, J. S. & Kwon, H. M. Tonicity-responsive enhancer binding protein, a Rel-like protein that stimulates transcription in response to hypertonicity. Proc. Natl Acad. Sci. USA 96, 2538–2542 (1999).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Lopez-Rodriguez, C. et al. Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression. Proc. Natl Acad. Sci. USA 101, 2392–2397 (2004).

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Nakayama, Y., Peng, T., Sands, J. M. & Bagnasco, S. M. The TonE/TonEBP pathways mediates tonicity-responsive regulation of UT-A urea transporter expression. J. Biol. Chem. 275, 38275–38280 (2000).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Choi, S. Y. et al. Tonicity-responsive enhancer-binding protein mediates hyperglycemia-induced inflammation and vascular and renal injury. J. Am. Soc. Nephrol. 29, 492–504 (2018).

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Boeger, C. A. et al. NFAT5 and SLC4A10 loci associate with plasma osmolality. J. Am. Soc. Nephrol. 28, 2311–2321 (2017).

    Article  Google Scholar 

  8. 8.

    Rosen, E. D. et al. Epigenetics and epigenomics: implications for diabetes and obesity. Diabetes 67, 1923–1931 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Semenza, G. L. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu. Rev. Pathol. 9, 47–71 (2013).

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Maouyo, D. et al. Mouse TonEBP-NFAT5: expression in early development and alternative splicing. Am. J. Physiol. 282, F802–F809 (2002).

    CAS  Google Scholar 

  11. 11.

    Lee, S. D., Colla, E., Sheen, M. R., Na, K. Y. & Kwon, H. M. Multiple domains of TonEBP cooperate to stimulate transcription in response to hypertonicity. J. Biol. Chem. 278, 47571–47577 (2003).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Kwon, M. S. et al. Novel nuclear localization signal regulated by ambient tonicity in vertebrates. J. Biol. Chem. 283, 22400–22409 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Raat, N. J., van Os, C. H. & Bindels, R. J. Effects of osmotic perturbation on [Ca2+]i and pHi in rabbit proximal tubular cells in primary culture. Am. J. Physiol. 269, F205–F211 (1995).

    CAS  PubMed  Google Scholar 

  14. 14.

    Stroud, J. C., Lopez-Rodriguez, C., Rao, A. & Chen, L. Structure of a TonEBP-DNA complex reveals DNA encircled by a transcription factor. Nat. Struct. Biol. 9, 90–94 (2002).

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Lee, S. D., Woo, S. K. & Kwon, H. M. Dimerization is required for phosphorylation and DNA binding of TonEBP/NFAT5. Biochem. Biophys. Res. Commun. 294, 968–975 (2002).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Kim, J. A. et al. Modulation of TonEBP activity by SUMO modification in response to hypertonicity. Front. Physiol. 5, 200 (2014).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Irarrazabal, C. R., Liu, J. C., Burg, M. B. & Feraris, J. D. ATM, a DNA dmage-inducible kinase, contributes to activation by high NaCl of the transcription factor TonEBP/OREBP. Proc. Natl Acad. Sci. USA 101, 8809–9914 (2004).

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Gallazzini, M. et al. High NaCl-induced activation of CDK5 increases phosphorylation of the osmoprotective transcription factor TonEBP/OREBP at threonine 135, which contributes to its rapid nuclear localization. Mol. Biol. Cell 22, 703–714 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Kang, H. J. et al. TonEBP regulates PCNA polyubiquitination in response to DNA damage through interaction with SHPRH and USP1. iScience 19, 177–190 (2019). This study details the dynamic interactions between TonEBP and enzymes of the ubiquitylation machinery, which lead to changes in PCNA ubiquitylation and DNA repair without affecting gene expression.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Lee, H. H. et al. LPS-induced NF-κB enhanceosome requires TonEBP/NFAT5 without DNA binding. Sci. Rep. 6, 24921 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Colla, E. et al. TonEBP is inhibited by RNA helicase A via interaction involving the E’F loop. Biochem. J. 393, 411–419 (2006).

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Irarrazabal, C. E. et al. Phospholipase C-γ1 is involved in signaling the activation by high NaCl of the osmoprotective transcription factor TonEBP/OREBP. Proc. Natl Acad. Sci. USA 107, 906–911 (2010).

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Woo, S. K., Dahl, S. C., Handler, J. S. & Kwon, H. M. Bidirectional regulation of tonicity-responsive enhancer binding protein in response to changes in tonicity. Am. J. Physiol. Renal Physiol. 278, F1006–F1012 (2000).

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Cai, Q., Ferraris, J. D. & Burg, M. B. High NaCl increases TonEBP/OREBP mRNA and protein by stabilizing its mRNA. Am. J. Physiol. Renal Physiol. 289, F803–F807 (2005).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Kojima, R. et al. Hypertonicity-induced expression of monocyte chemoattractant protein-1 through a novel cis-acting element and MAPK signaling pathways. J. Immunol. 184, 5253–5262 (2010).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Gallazzini, M., Yu, M. J., Gunaratne, R., Burg, M. B. & Ferraris, J. D. c-Abl medicates high NaCl-induced phosphorylation and activation of the transcription factor TonEBP/OREBP. FASEB J. 24, 4325–4335 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Zhang, Z. et al. Ataxia telangiectasia-mutated, a DNA damage-inducible kinase, contributes to high NaCl-induced nuclear localization of transcription factor TonEBP/OREBP. Am. J. Physiol. Renal Physiol. 289, F506–F511 (2005).

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Zhou, X., Ferraris, J. D. & Burg, M. B. Mitochondrial reactive oxygen species contribute to high NaCl-induced activation of the transcription factor TonEBP/OREBP. Am. J. Physiol. Renal Physiol. 290, F1169–F1176 (2006).

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Choi, S. et al. Transcription factor NFAT5 promotes macrophage survival in rheumatoid arthritis. J. Clin. Invest. 127, 954–969 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Buxade, M. et al. Gene expression induced by Toll-like receptors in macrophages requires the transcription factor NFAT5. J. Exp. Med. 209, 379–393 (2012). This study reveals the role of TonEBP in antimicrobial immunity.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Yoo, E. J. et al. TonEBP suppresses the HO-1 gene by blocking recruitment of Nrf2 to its promoter. Front. Immunol. 10, 850 (2019). This study defines the suppression of anti-inflammatory polarization of macrophages by TonEBP at the molecular level.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Choi, S. Y. et al. TonEBP suppresses IL-10-mediated immunomodulation. Sci. Rep. 6, 25726 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Jeong, G. R. et al. Inflammatory signals induce the expression of tonicity-responsive enhancer binding protein (TonEBP) in microglia. J. Neuroimmunol. 295–296, 21–29 (2016).

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    Lee, J. H. et al. Tonicity-responsive enhancer-binding protein promotes hepatocellular carcinogenesis, recurrence and metastasis. Gut 68, 347–358 (2019). This study shows that TonEBP is a strong biomarker of recurrence and mortality in patients with HCC.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Zhai, S., Li, M., Sun, B. & Han, Y. Amelioration of lipopolysaccharide-induced nephrotic proteinuria by NFAT5 depletion involves suppressed NF-κB activity. Inflammation 42, 1326–1335 (2019).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Villanueva, S. et al. NFAT5 is activated by hypoxia: role of ischemia and reperfusion in the rat kidney. PLoS One 7, e39665 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Zhou, B. et al. Hypertonic induction of aquaporin-5: novel role of hypoxia-inducible factor-1alpha. Am. J. Physiol. Cell Physiol. 292, C1280–C1290 (2007).

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Yoo, E. J. et al. Transcriptional regulator TonEBP mediates oxidative damages in ischemic kidney injury. Cell 8, 1284 (2019). This study provides insights into the involvement of the TonEBP pathway in mitochondrial dysfunction and ROS in proximal tubule injury.

    CAS  Article  Google Scholar 

  39. 39.

    Mak, K. M. C. et al. Nuclear factor of activated T cells 5 deficiency increases the severity of neuronal cell death in ischemic injury. Neurosignals 20, 237–251 (2012).

    CAS  PubMed  Google Scholar 

  40. 40.

    Neubert, P. et al. HIF1A and NFAT5 coordinate Na+-boosted antibacterial defense via enhanced autophagy and autolysosomal targeting. Autophagy 15, 1899–1916 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Halterman, J. A., Kwon, H. M., Leitinger, N. & Wamhoff, B. R. NFAT5 expression in bone marrow-derived cells enhances atherosclerosis and drives macrophage migration. Front. Physiol. 3, 313 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Lee, H. H. et al. TonEBP/NFAT5 promotes obesity and insulin resistance by epigenetic suppression of white adipose tissue beiging. Nat. Commun. 10, 3536 (2019). This study defines the role of TonEBP in the risk of obesity and T2DM at the molecular level.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. 43.

    Xie, H., Lim, B. & Lodish, H. F. MicroRNAs induced during adipogenesis that accelerate fat cell development are downregulated in obesity. Diabetes 58, 1050–1057 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Hosogai, N. et al. Adipose tissue hypoxia in obesity and its impact on adipokine dysregulation. Diabetes 56, 901–911 (2007).

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Hinske, L. C. et al. Intronic miRNA-641 controls its host gene’s pathway PI3K/AKT and this relationship is dysfunctional in glioblastoma multiforme. Biochem. Biophys. Res. Commun. 489, 477–483 (2017).

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Tao, H. et al. NFAT5 is regulated by p53/miR-27a signal axis and promotes mouse ovarian granulosa cells proliferation. Int. J. Biol. Sci. 15, 287–297 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Meng, X., Li, Z., Zhou, S., Xiao, S. & Yu, P. miR-194 suppresses high glucose-induced non-small cell lung cancer cell progression by targeting NFAT5. Thorac. Cancer 10, 1051–1059 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Li, W. et al. MiR-568 inhibits the activation and function of CD4+ T cells and Treg cells by targeting NFAT5. Int. Immunol. 26, 269–281 (2014).

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Ying, W. et al. MicroRNA-223 is a crucial mediator of PPARγ-regulated alternative macrophage activation. J. Clin. Invest. 125, 4149–4159 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Xin, Y. et al. miR-20b inhibits T cell proliferation and activation via NFAT signaling pathway in thymoma-associated myasthenia gravis. Biomed. Res. Int. 2016, 9595718 (2016).

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Kästle, M. et al. MicroRNA cluster 106a~363 is involved in T helper 17 cell differentiation. Immunology 152, 402–413 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52.

    Ge, G. et al. miR-10b-5p regulates C2C12 myoblasts proliferation and differentiation. Biosci. Biotechnol. Biochem. 83, 291–299 (2019).

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Neuhofer, W. et al. Regulation of TonEBP transcriptional activator in MDCK cells following changes in ambient tonicity. Am. J. Physiol. 283, C1604–C1611 (2002).

    CAS  Article  Google Scholar 

  54. 54.

    Berry, M. R. et al. Renal sodium gradient orchestrates a dynamic antibacterial defense zone. Cell 170, 860–874 (2017). This study details how medullary hypertonicity provides protection from ascending infection through the actions of TonEBP.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Manchnik, A. et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat. Med. 15, 545–552 (2009). This paper describes how TonEBP signalling in macrophages mediates sodium removal and blood pressure homeostasis in the skin.

    Article  CAS  Google Scholar 

  56. 56.

    Jantsch, J. et al. Cutaneous Na+ storage strengthens the antimicrobial barrier function of the skin and boosts macrophage-driven host defense. Cell Metab. 21, 493–501 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Berga-Bolanos, R., Drews-Elger, K., Aramburu, J. & Lopez-Rodriguez, C. NFAT5 regulates T lymphocyte homeostatis and CD24-dependent T cell expansion under pathologic hypernatremia. J. Immunol. 185, 6624–6635 (2010).

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Go, W. Y., Liu, X., Roti, M. A., Liu, F. & Ho, S. N. NFAT5/TonEBP mutant mice define osmotic stress as a critical feature of the lymphoid microenvironment. Proc. Natl Acad. Sci. USA 101, 10673–10678 (2004).

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Tellechea, M., Buxade, M., Tejedor, S., Aramburu, J. & Lopez-Rodriguez, C. NFAT5-regulated macrophage polarization supports the proinflammatory function of macrophages and T lymphocytes. J. Immunol. 200, 305–315 (2018).

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Buxade, M. et al. Macrophage-specific MHCII expression is regulated by a remote Ciita enhancer controlled by NFAT5. J. Exp. Med. 215, 2901–2918 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V. K. IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485–517 (2009).

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Kleinewiefeld, M. et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496, 518–522 (2013). This study reports the first connection of TonEBP with pathological CD4 + T cell differentiation and autoimmunity.

    Article  CAS  Google Scholar 

  63. 63.

    Vandenbark, A. A. & Offner, H. Critical evaluation of regulatory T cells in autoimmunity: are the most potent regulatory specificities being ignored? Immunology 125, 1–13 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Matthias, J. et al. Sodium chloride is an ionic checkpoint for human TH2 cells and shapes the atopic skin microenvironment. Sci. Transl Med. 11, 480 (2019).

    Article  CAS  Google Scholar 

  65. 65.

    Schwartz, L. et al. Is inflammation a consequence of extracellular hyperosmolarity? J. Inflamm. 6, 21 (2009).

    Article  Google Scholar 

  66. 66.

    Roth, I. et al. Osmoprotective transcription factor NFAT5/TonEBP modulates nuclear factor-κB activity. Mol. Biol. Cell. 21, 3459–3474 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Farabaugh, K. T. et al. Protein kinase R mediates the inflammatory response induced by hyperosmotic stress. Mol. Cell Biol. 37, e00521-16 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Serr, I. et al. A miRNA181a/NFAT5 axis links impaired T cell tolerance induction with autoimmune type 1 diabetes. Sci. Transl Med. 10, eaag1782 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. 69.

    Yoon, H. J. et al. NFAT5 is a critical regulator of inflammatory arthritis. Arthritis Rheum. 63, 1843–1852 (2011).

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Lee, S. et al. Transcription factor NFAT5 promotes migration and invasion of rheumatoid synoviocytes via coagulation factor III and CCL2. J. Immunol. 201, 359–370 (2018).

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    El-Serag, H. B. Hepatocellular carcinoma. N. Eng. J. Med. 365, 1118–1127 (2011).

    CAS  Article  Google Scholar 

  72. 72.

    Fox, C. S. et al. Trends in cardiovascular complication of diabetes. JAMA 292, 2495–2499 (2004).

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Goettgen, A. et al. New loci associated with kidney function and chronic kidney disease. Nat. Genet. 42, 376–384 (2010).

    Article  CAS  Google Scholar 

  74. 74.

    Mahajan, A. et al. Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenomic maps. Nat. Genet. 50, 1505–1513 (2018). This study provides the first genetic evidence for an association between TONEBP polymorphisms and risk of T2DM.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Kavanagh, D. H. et al. Haplotype association analysis of genes within the WNT signaling pathways in diabetic nephropathy. BMC Nephrol. 14, 126 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Tragante, V. et al. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci. Am. J. Hum. Genet. 94, 349–360 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Parsa, A. et al. Genotype-based changes in serum uric acid affect blood pressure. Kidney Int. 81, 502–507 (2012).

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Goettgen, A. et al. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat. Genet. 45, 145–154 (2013).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Work in the laboratory of H.M.K. was supported by the National Research Foundation grants 2018R1A5A1024340, 2017R1E1A1A01074673 and NRF-2019R1A2C1089260.

Author information

Affiliations

Authors

Contributions

H.M.K., S.Y.C. and W.L.-K. researched the data for the article, contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission; H.M.K. and S.Y.C. wrote the manuscript.

Corresponding author

Correspondence to Hyug Moo Kwon.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Nephrology thanks W. Neuhofer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Choi, S.Y., Lee-Kwon, W. & Kwon, H.M. The evolving role of TonEBP as an immunometabolic stress protein. Nat Rev Nephrol 16, 352–364 (2020). https://doi.org/10.1038/s41581-020-0261-1

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing