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Mol Biol Cell. 2018 Feb 15;29(4):499-509. doi: 10.1091/mbc.E17-08-0529. Epub 2017 Dec 13.

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

Author information

1
Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
2
Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA 15213.
3
Department of Internal Medicine, Division of Nephrology, University of Iowa Carver College of Medicine, Iowa City, IA 52242.
4
Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
5
Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 ars129@pitt.edu.
6
VA Pittsburgh Healthcare System, Pittsburgh, PA 15240.

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.

PMID:
29237822
PMCID:
PMC6014176
DOI:
10.1091/mbc.E17-08-0529
[Indexed for MEDLINE]
Free PMC Article

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