The evolving role of TonEBP as an immunometabolic stress protein


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.

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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.


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

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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.

Correspondence to Hyug Moo Kwon.

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

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Choi, S.Y., Lee-Kwon, W. & Kwon, H.M. The evolving role of TonEBP as an immunometabolic stress protein. Nat Rev Nephrol (2020).

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