PMID:23453970

Citation	Wakabayashi, M, Mori, T, Isobe, K, Sohara, E, Susa, K, Araki, Y, Chiga, M, Kikuchi, E, Nomura, N, Mori, Y, Matsuo, H, Murata, T, Nomura, S, Asano, T, Kawaguchi, H, Nonoyama, S, Rai, T, Sasaki, S and Uchida, S (2013) Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension. Cell Rep 3:858-68
Abstract	Mutations in WNK kinases cause the human hypertensive disease pseudohypoaldosteronism type II (PHAII), but the regulatory mechanisms of the WNK kinases are not well understood. Mutations in kelch-like 3 (KLHL3) and Cullin3 were also recently identified as causing PHAII. Therefore, new insights into the mechanisms of human hypertension can be gained by determining how these components interact and how they are involved in the pathogenesis of PHAII. Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level. The reduced interaction of KLHL3 and WNK4 by PHAII-causing mutations in either protein reduced the ubiquitination of WNK4, resulting in an increased level of WNK4 protein. Transgenic mice overexpressing WNK4 showed PHAII phenotypes, and WNK4 protein was indeed increased in Wnk4(D561A/+) PHAII model mice. Thus, WNK4 is a target for KLHL3-mediated ubiquitination, and the impaired ubiquitination of WNK4 is a common mechanism of human hereditary hypertension.
Links	PubMed Online version:10.1016/j.celrep.2013.02.024
Keywords	Animals; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cullin Proteins/metabolism; HEK293 Cells; Humans; Mice; Mutation; Phenotype; Protein Binding; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; Pseudohypoaldosteronism/etiology; Pseudohypoaldosteronism/genetics; Pseudohypoaldosteronism/metabolism; Transcription, Genetic; Ubiquitination
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:WNK4	involved_in	GO:0050801: ion homeostasis	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:WNK4	involved_in	GO:0070294: renal sodium ion absorption	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:WNK4	involved_in	GO:0072156: distal tubule morphogenesis	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:WNK4	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q9UH77	F		Seeded From UniProt	complete
HUMAN:KLHL3	part_of	GO:0031463: Cul3-RING ubiquitin ligase complex	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:KLHL3	involved_in	GO:0016567: protein ubiquitination	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:KLHL3	involved_in	GO:0006511: ubiquitin-dependent protein catabolic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:KLHL3	involved_in	GO:0050801: ion homeostasis	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:KLHL3	involved_in	GO:0070294: renal sodium ion absorption	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:KLHL3	involved_in	GO:0072156: distal tubule morphogenesis	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:KLHL3	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q96J92	F		Seeded From UniProt	complete
HUMAN:CUL3	part_of	GO:0031463: Cul3-RING ubiquitin ligase complex	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete

References

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