Potassium-regulated distal tubule WNK bodies are kidney-specific WNK1 dependent

Abstract

WNK bodies are large punctate membraneless cytosolic signaling foci that sequester WNK serine–threonine kinases and form in renal distal tubular epithelial cells during shifts in total body potassium balance. The assembly of these structures requires KS-WNK1, a truncated isoform of the WNK1 gene that is exclusively expressed in the distal tubule.

Abstract

With-no-lysine (WNK) kinases coordinate volume and potassium homeostasis by regulating renal tubular electrolyte transport. In the distal convoluted tubule (DCT), potassium imbalance causes WNK signaling complexes to concentrate into large discrete foci, which we call “WNK bodies.” Although these structures have been reported previously, the mechanisms that drive their assembly remain obscure. Here, we show that kidney-specific WNK1 (KS-WNK1), a truncated kinase-defective WNK1 isoform that is highly expressed in the DCT, is critical for WNK body formation. While morphologically distinct WNK bodies were evident in the distal tubules of mice subjected to dietary potassium loading and restriction, KS-WNK1 knockout mice were deficient in these structures under identical conditions. Combining in vivo observations in kidney with reconstitution studies in cell culture, we found that WNK bodies are dynamic membraneless foci that are distinct from conventional organelles, colocalize with the ribosomal protein L22, and cluster the WNK signaling pathway. The formation of WNK bodies requires an evolutionarily conserved cysteine-rich hydrophobic motif harbored within a unique N-terminal exon of KS-WNK1. We propose that WNK bodies are not pathological aggregates, but rather are KS-WNK1–dependent microdomains of the DCT cytosol that modulate WNK signaling during physiological shifts in potassium balance.