Impaired KLHL3-Mediated Ubiquitination of WNK4 Causes Human Hypertension

SummaryMutations 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 Wnk4D561A/+ 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.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► WNK4 kinase is a substrate of KLHL3-Cullin3-targeted ubiquitination
► PHAII-causing mutations of WNK4, KLHL3, and Cullin3 decrease WNK4 ubiquitination
► Impaired WNK4 ubiquitination activates the OSR1/SPAK-NCC axis and causes hypertension