NRBP1 and TSC22D proteins affect distal convoluted tubule physiology through modulation of the WNK pathway.

The with-no-lysine (K) (WNK) kinases regulate processes such as cell volume and epithelial ion transport through the modulation of cation chloride cotransporters such as the NaCl cotransporter (NCC) present in the distal convoluted tubule (DCT) of the kidney. Recently, the interaction of WNKs with nuclear receptor binding protein 1 (NRBP1) and transforming growth factor-β-stimulated clone 22 domain (TSC22D) proteins was reported. Here, we explored the effect of NRBP1 and TSC22Ds on WNK signaling in vitro and in the DCT. TSC22D1.1, TSC22D2, and NRBP1 are localized in DCT WNK bodies, which are cytoplasmic biomolecular condensates associated with WNK activation. In HEK293 cells, long TSC22D isoforms and NRBP1 increase WNK4 activity. DCT-specific NRBP1-knockout mice have reduced NCC phosphorylation and activate a compensatory response. Thus, NRBP1 and long TSC22D proteins are positive modulators of WNK signaling and modulate Na reabsorption in the kidney. NRBP1 and TSC22Ds likely influence WNK signaling in other tissues, affecting various physiological processes.