Tonicity-independent regulation of the osmosensitive transcription factor TonEBP (NFAT5)

Abstract

Tonicity-responsive enhancer binding protein (TonEBP/nuclear factor of activated T-cells 5 [NFAT5]) is a Rel homology transcription factor classically known for its osmosensitive role in regulating cellular homeostasis during states of hypo- and hypertonic stress. A recently growing body of research indicates that TonEBP is not solely regulated by tonicity, but that it can be stimulated by various tonicity-independent mechanisms in both hypertonic and isotonic tissues. Physiological and pathophysiological stimuli such as cytokines, growth factors, receptor and integrin activation, contractile agonists, ions, and reactive oxygen species have been implicated in the positive regulation of TonEBP expression and activity in diverse cell types. These new data demonstrate that tonicity-independent stimulation of TonEBP is critical for tissue-specific functions like enhanced cell survival, migration, proliferation, vascular remodeling, carcinoma invasion, and angiogenesis. Continuing research will provide a better understanding as to how these and other alternative TonEBP stimuli regulate gene expression in both health and disease.

Fig. 1.

Physiological and pathophysiological stimuli regulate tonicity-responsive enhanced binding protein (TonEBP) in diverse cell types. Novel, tonicity-independent stimuli regulate TonEBP expression, transactivation, nuclear translocation, reporter activity, and downstream TonEBP-dependent gene activation. Solid lines represent more defined signaling cascades, whereas dashed lines represent less defined pathways. In T-cells, T-cell receptor activation and PMA + ionomycin (a calcium ionophore) upregulate TonEBP expression and activity via the calcineurin (CaN) pathway. CaN inhibitors cyclosporine A (CsA) and FK506 block T-cell receptor and PMA + ionomycin stimulation of TonEBP. In carcinomas, α6β4 integrin clustering stimulates TonEBP expression and activity leading to enhanced s100 calcium binding protein a4 (s100a4) gene expression and increased carcinoma migration and invasion. TPA + ionomycin stimulation also upregulates TonEBP activity in carcinomas. In nucleus pulposus cells of the intervertebral disc, PMA + ionomycin stimulates TonEBP expression, independent of calcineurin, which leads to increased β1,3-glucuroosyltransferase-I (GlcAT-I) gene expression. Bone morphogenetic protein 2 (BMP-2) and transforming growth factor β (TFG-β) both upregulate TonEBP expression and transactivation in nucleus pulposus cells resulting in increased GlcAT-1 expression. In fibroblast-like synoviocytes within rheumatoid arthritic joints, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) upregulate TonEBP expression resulting in fibroblast-like synoviocyte proliferation and increased cell survival. In vascular smooth muscle cells, angiotensin II stimulates TonEBP nuclear translocation and activity independent of calcineurin, which results in increased smooth muscle α-actin (SMαA) gene expression. Also in vascular smooth muscle cells, platelet-derived growth factor BB (PDGF-BB) upregulates TonEBP expression and activity, independent of calcineurin, leading to increased smooth muscle cell migration. In kidney cells, superoxide + NaCl-induced hypertonicity augments TonEBP transactivation and activity resulting in increased expression of the sodium chloride/betaine cotransporter (BGT1) gene and increased kidney cell survival. Also in kidney cells, nitric oxide increases TonEBP S-nitrosylation leading to decreased TonEBP activity, inhibited expression of aldose reductase (AR), and sodium/myoinositol cotransporter (SMIT) gene expression and is believed to contribute to diuresis.