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PHA2D proteins, KLHL3‐CUL3 and WNK1, Form An Endocytic Switch Signal that Controls the Renal K+ Excretory Channel, ROMK
Author(s) -
Welling Paul,
Kim BoYoung,
Wade James B,
Coleman Richard,
Fang Liang
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.912.13
Subject(s) - microbiology and biotechnology , endocytic cycle , endocytosis , distal convoluted tubule , potassium channel , biology , chemistry , nephron , biophysics , biochemistry , endocrinology , kidney , receptor
Mutations in Kelch like 3 (KLHL3) and Cullin 3 (CUL3) have been recently reported to cause a familial disorder of hyperkalemia and hypertension (Pseudohypoaldosteronism type II, PHAII) but the precise mechanism remains unclear. Here, we report that KLHL3/CUL3 and another PHAII gene, WNK1, tune endocytosis of the Renal Potassium channel, ROMK, by regulating the clathrin adaptor, ARH. We found that KLHL3 and CUL3 are critical subunits of a ubiquitin ligase complex that controls ARH abundance in the distal nephron. CUL3 interacts with ARH in a KLHL3‐dependent manner, driving ubiquitination and proteasomal degradation of ARH to limit ROMK endocytosis in states of dietary potassium excess. WNK1, which is activated in states of potassium restriction, stimulates phosphorylation of ARH at S14 and this prevents rapid degradation of ARH by KLHL3/CUL3. Thus, KLHL3/CUL3 and WNK1 exert opposing activities on ARH to control ROMK abundance on the apical surface in concert with physiological demands. Uncontrolled activation of ARH and ROMK endocytosis provides an explanation for urinary potassium retention and hyperkalemia in PHAII.