GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com


Jump to: navigation, search


You don't have sufficient rights on this wiki to edit tables. Perhaps you need to log in. Changes you make in the Table editor will not be saved back to the wiki

See Help for Help on this wiki. See the documentation for how to use the table editor


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


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.


PubMed Online version:10.1016/j.celrep.2013.02.024


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