WNK kinase activity is modulated by the pseudokinase NRBP1 and the scaffold proteins of the TSC22D family.

Purpose of review: With No lysine (WNK) kinases participate in maintaining the homeostasis of water and electrolytes, by regulating the Cation Chloride Cotransporters (CCCs), which are implicated in the regulation of cell volume, neuronal intracellular [Cl-], and regulation of salt balance by the kidneys. Recently, the Nuclear Receptor Binding Proteins (NRBP) and the TGF-β-Stimulated Clone 22 Domain family (TSC22D) proteins were identified as WNK interactors that modulate WNK kinase activity. This review will summarize the findings of recent works that explore this previously unrecognized role of NRBP and TSC22D proteins.

Recent findings: Three groups independently described the interaction between components of the WNK/SPAK-OSR1 pathway and NRBP1 or the TSC22D proteins, which are known interactors of NRBP1. These proteins were shown to colocalize with WNK kinases in biomolecular condensates. It was described that NRBP1 and TSC22D proteins have an activating effect on WNK activity and that its deficiency leads to impaired cell volume regulation and impaired electrolyte transport regulation in the distal convoluted tubule.

Summary: These findings have implications extending beyond epithelial sodium transport, as they may be relevant for other fundamental processes modulated by WNKs, such as neuronal function, cellular volume regulation, and cell proliferation.