Brx, a link between osmotic stress, inflammation and organ physiology/pathophysiology

Abstract

Dehydration, and consequent intracellular hyperosmolarity, is a major challenge to land organisms as it is associated with extraction of water from cells and disturbance of global cellular function. Organisms have thus developed a highly conserved regulatory mechanism that transduces the hyperosmolarity signal from the cell surface to the cell nucleus and adjusts the expression of cellular osmolarity-regulating genes. We recently found that the Rho-type guanine nucleotide exchange factor Brx, or AKAP13, is essential for osmotic stress-stimulated expression of nuclear factor of activated T cells 5 (NFAT5), a key transcription factor of intracellular osmolarity. It accomplishes this by first attracting cJun kinase-interacting protein 4 and then coupling activated Rho-type small G-proteins to cascade components of the p38 MAPK signaling pathway, ultimately activating NFAT5. We describe the potential implications of osmotic stress and Brx activation in organ physiology and pathophysiology and connect activation of this system to key human homeostatic states.

Keywords::

• cJun kinase-interacting protein
• glucocorticoid receptor
• glucocorticoids
• guanine nucleotide exchange factor
• hyperosmolarity
• mitogen-activated protein kinase
• nuclear factor of activated T cells 5
• small GTP-binding protein

Financial & competing interests disclosure

This work is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA, and the University of Athens, Athens, Greece. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.