TonEBP

TonEBP, or tonicity-responsive enhancer-binding protein, is a transcription factor in mammals. It is also known as NFAT5 (nuclear factor of activated T cells 5) and OREBP (osmotic response element-binding protein). It belongs to the NFAT family but is unique in its activation by osmotic stress rather than canonical calcium/calcineurin signaling.

TonEBP functions as the central regulator of cellular responses to hypertonic environments. Upon exposure to hypertonicity, TonEBP becomes activated, translocates to the nucleus, and binds to tonicity-responsive enhancer elements (TonE) found in the promoters of a suite of osmoprotective genes. Key targets include aldose reductase (AR), the betaine transporter BGT-1 (SLC6A12), the taurine transporter TauT (SLC6A6) and the myo-inositol transporter SMIT. Upregulation of these genes promotes accumulation of compatible osmolytes that protect cell volume and function.

Expression of TonEBP is broad but is particularly high in tissues that experience high extracellular osmolality, such as the renal medulla. In addition to osmoregulation, TonEBP influences immune and inflammatory pathways in certain cell types, and can regulate non-osmotic genes through interaction with other transcriptional regulators.

Regulation involves phosphorylation and modulation by signaling pathways activated by osmotic stress, notably p38 MAP kinase, and it can be influenced by cellular context and co-regulators. The protein contains a Rel-like DNA-binding domain characteristic of NFAT family members and a transactivation domain that mediates transcriptional activation.