Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension.
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| 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.
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| Authors | Mai Wakabayashi, Takayasu Mori, Kiyoshi Isobe, Eisei Sohara, Koichiro Susa, Yuya Araki, Motoko Chiga, Eriko Kikuchi, Naohiro Nomura, Yutaro Mori, Hiroshi Matsuo, Tomohiro Murata, Shinsuke Nomura, Takako Asano, Hiroyuki Kawaguchi, Shigeaki Nonoyama, Tatemitsu Rai, Sei Sasaki, Shinichi Uchida |
| Journal | Cell reports (Cell Rep) Vol. 3 Issue 3 Pg. 858-68 (Mar 28 2013) ISSN: 2211-1247 [Electronic] United States |
| PMID | 23453970 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
| Copyright | Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved. |
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