Beyond ion homeostasis: WNK1 and the role of water influx in T cell biology

The serine-threonine kinase WNK1 is a regulator of ion homeostasis and cell volume control studied most extensively in the kidney. WNK1 phosphorylates and activates the OXSR1 and STK39 kinases, which in turn phosphorylate members of the SLC12A-family of ion co-transporters resulting in influx of Na + , K + and Cl - ions and subsequent osmotically-driven water entry through aquaporins and an increase in cell volume. This WNK1-regulated pathway restores cell volume following shrinkage caused by exposure to hyperosmotic conditions, a process termed regulatory volume increase (RVI). Unexpectedly, we discovered that WNK1 regulates multiple aspects of T cell biology. During thymic development, WNK1-deficient thymocytes fail to progress beyond the β-selection checkpoint. In mature CD4 + T cells, WNK1 is required for T cell migration and homing to secondary lymphoid organs. During T cell activation, WNK1 is required for proliferation. Mechanistically, we showed that T cell antigen receptor (TCR) and chemokine receptor signalling in CD4 + T cells cause activation of WNK1 resulting in ion and water influx. Furthermore, this WNK1-induced water influx is required for chemokine-induced migration and for entry into cell cycle during T cell activation, illustrating the importance of water uptake in T cell biology. However, it remains unclear how WNK1 is activated downstream of the TCR and chemokine receptors, and how water entry affects intracellular signalling pathways. In this review, we summarise the current knowledge of WNK1 signalling in T cells and discuss how WNK1 may be activated, and whether localised changes in water content might modulate spatially-restricted signalling events in T cells.