TY - JOUR
T1 - Potassium-regulated distal tubule WNK bodies are kidney-specific WNK1 dependent
AU - Boyd-Shiwarski, Cary R.
AU - Shiwarski, Daniel J.
AU - Roy, Ankita
AU - Namboodiri, Hima N.
AU - Nkashama, Lubika J.
AU - Xie, Jian
AU - McClain, Kara L.
AU - Marciszyn, Allison
AU - Kleyman, Thomas R.
AU - Tan, Roderick J.
AU - Stolz, Donna B.
AU - Puthenveedu, Manojkumar A.
AU - Huang, Chou Long
AU - Subramanya, Arohan R.
N1 - Publisher Copyright:
© 2018 Boyd-Shiwarski et al.
PY - 2018/2/15
Y1 - 2018/2/15
N2 - 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.
AB - 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.
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U2 - 10.1091/mbc.E17-08-0529
DO - 10.1091/mbc.E17-08-0529
M3 - Article
C2 - 29237822
AN - SCOPUS:85042209949
SN - 1059-1524
VL - 29
SP - 499
EP - 509
JO - Molecular biology of the cell
JF - Molecular biology of the cell
IS - 4
ER -