School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
Nat Rev Nephrol. 2020 Jun;16(6):352-364. doi: 10.1038/s41581-020-0261-1. Epub 2020 Mar 10.
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.
张力反应增强结合蛋白（TonEBP），也称为激活 T 细胞核因子 5（NFAT5），二十年前在研究肾脏髓质细胞对高渗（高渗透压）应激的反应时被发现是一种转录调节因子。此后的大量研究表明，TonEBP 是一种多功能应激蛋白，参与多种免疫代谢疾病。TONEBP 内含子中的一些单核苷酸多态性（SNP）是顺式表达数量性状基因座，影响 TONEBP 转录。这些 SNP 与 2 型糖尿病、糖尿病肾病、炎症、高血压和异常血浆渗透压的风险增加相关，表明 TONEBP 表达的变化可能导致这些表型。此外，功能研究表明，TonEBP 参与类风湿关节炎、动脉粥样硬化、糖尿病肾病、急性肾损伤、高脂血症和胰岛素抵抗、自身免疫性疾病（包括 1 型糖尿病和多发性硬化症）、盐敏感性高血压和肝细胞癌的发病机制。TonEBP 的这些病理活性与 TonEBP 对高渗、细菌感染和遗传毒素诱导的 DNA 损伤的保护作用形成对比。一个新出现的主题是，TonEBP 是一种应激蛋白，介导细胞对一系列病理损伤的反应，包括过量的热量摄入、炎症和氧化应激。
