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PMID:23453970

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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

Significance

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

Notes

See also

References

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