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Kelchlike three and Cullin three regulate electrolyte homeostasis via ubiquitination and degradation of WNKShigeru Shibataa,b, Junhui Zhanga,b, Jeremy Puthumanaa,b, Kathryn L. Stonec, and Richard P. Liftona,b,aDepartment of Genetics, bHoward Hughes Medical Institute, and cW. M. Keck Facility, Yale University College of Medicine, New Haven, CTContributed by Richard P. Lifton, March 8, 2013 (sent for critique February 25, 2013)Pseudohypoaldosteronism form II (PHAII) is usually a rare Mendelian syndrome featuring hypertension and hyperkalemia resulting from constitutive renal salt reabsorption and impaired K secretion. Lately, mutations in Kelchlike three (KLHL3) and Cullin three (CUL3), components of an E3 ubiquitin ligase complex, have been identified to trigger PHAII, suggesting that loss of this complex’s capability to target particular substrates for ubiquitination results in PHAII. By MS and coimmunoprecipitation, we show that KLHL3 normally binds to WNK1 and WNK4, members of WNK (with no lysine) kinase household which have previously been discovered mutated in PHAII. We show that this binding leads to ubiquitination, including polyubiquitination, of at the very least 15 distinct web sites in WNK4, resulting in reduced WNK4 levels. Dominant diseasecausing mutations in KLHL3 and WNK4 each impair WNK4 binding, ubiquitination, and degradation. WNK4 generally induces clearance of the renal outer medullary K channel (ROMK) from the cell surface. We show that WT but not mutant KLHL3 inhibits WNK4induced reduction of ROMK level.Boc-NH-PEG3 site We show that PHAIIcausing mutations in WNK4 bring about a marked raise in WNK4 protein levels inside the kidney in vivo.Buy1252793-57-9 These findings demonstrate that CUL3 ING (truly interesting new gene) ligases that contain KLHL3 target ubiquitination of WNK4 and thereby regulate WNK4 levels, which in turn regulate levels of ROMK.PMID:23891445 These findings reveal a precise role of CUL3 and KLHL3 in electrolyte homeostasis and deliver a molecular explanation for the effects of diseasecausing mutations in each KLHL3 and WNK4.proteomics| Gordon syndrome | Kir1.ypertension impacts 1 billion folks worldwide and is usually a principal reversible danger aspect for cardiovascular disease. Identification from the causes of uncommon Mendelian types of hypertension has demonstrated the important part of improved renal salt reabsorption inside the pathogenesis of this common disease (1, 2). Among Mendelian hypertensive syndromes, pseudohypoaldosteronism type II (PHAII, also referred to as familial hypertensive hyperkalemia, Gordon syndrome, OMIM no. 145260) is especially in.
