Brx shines a light on the route from hyperosmolarity to NFAT5.

Nuclear factor of activated T cells 5 (NFAT5) is a member of the Rel family of transcription factors and is an essential inducer of osmoprotective gene products in mammalian cells. Its activation by hypertonicity requires p38 mitogen-activated protein kinase (MAPK) signaling and other pathways. A study now elucidates a signaling cascade regulated by the guanine nucleotide exchange factor Brx that leads to the activation of p38alpha MAPK and the induction of nfat5 messenger RNA in response to osmotic stress in lymphocytes and renal medullary cells. Brx-deficient lymphocytes showed impaired responses to hypertonicity, and brx(+/-) mice exhibited immune defects similar to those of nfat5-deficient mice. These findings support a major role for Brx in regulating the osmoprotective function of NFAT5 in different cell types.