title: Degradation by Cullin 3 and effect on WNK kinases suggest a role of KLHL2 in the pathogenesis of Familial Hyperkalemic Hypertension.
abstract: Mutations in WNK1 and WNK4, and in components of the Cullin-Ring Ligase system, kelch-like 3 (KLHL3) and Cullin 3 (CUL3), can cause the rare hereditary disease, Familial Hyperkalemic Hypertension (FHHt). The disease is characterized by overactivity of the renal sodium chloride cotransporter (NCC), which is phosphorylated and activated by the WNK-stimulated Ste20-type kinases, SPAK and OSR1. WNK kinases themselves can be targeted for ubiquitination and degradataion by the CUL3-KLHL3 E3 ubiquitin ligase complex. It is unclear, however, why there are significant differences in phenotypic severity among FHHt patients with mutations in different genes. It was reported that kelch-like 2 (KLHL2), a homolog of KLHL3, can also target WNK kinases for ubiquitation and degradation, and may play a special role in the systemic vasculature. Our recent study revealed the disease mutant CUL3 exhibits enhanced degradation of its adaptor protein KLHL3, potentially resulting in accumulation of WNK kinases secondarily. To investigate if KLHL2 plays a role in FHHt, we studied the effect of wild type and FHHt mutant CUL3 on degradation of KLHL2 and WNK kinase proteins in HEK293 cells. Although CUL3 facilitates KLHL2 degradation, the disease mutant CUL3 is more active in this regard. KLHL2 facilitated the degradation of wild type but not disease mutant WNK4 protein. These results suggest that KLHL2 likely plays a role in the pathogenesis of FHHt, and aggravates the phenotype caused by mutations in CUL3 and WNK4.
authors.affiliation: Department of Nephrology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: zhangchongzc@gmail.com.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Meermeier
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Terker
authors.affiliation: Institut für Vegetative Anatomie Charité - Universitätsmedizin Berlin Campus Charité-Mitte, Berlin, Germany.
authors.forename: Katharina I
authors.initials: KI
authors.lastname: Blankenstein
authors.affiliation: Department of Biology, Portland State University, Portland, OR, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Singer
authors.affiliation: Paris Cardiovascular Research Center, Paris, France; Faculty of Medicine, University Paris-Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Hadchouel
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR, USA; Portland VA Medical Center, Portland, OR, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Ellison
authors.affiliation: Division of Nephrology and Hypertension, Department of Medicine, Oregon Health and Science University, Portland, OR, USA. Electronic address: yangch@ohsu.edu.
authors.forename: Chao-Ling
authors.initials: CL
authors.lastname: Yang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D044842:Cullin Proteins / Q000378:metabolism*; D018450:Disease Progression; D066298:In Vitro Techniques; D007684:Kidney Tubules / Q000378:metabolism*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011546:Pseudohypoaldosteronism / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C503646:Cul3 protein, mouse; D044842:Cullin Proteins; C000598025:KLHL3 protein, mouse; C120754:Klhl2 protein, mouse; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases
keywords: Cullin 3; Degradation; Familial Hyperkalemic Hypertension; Kelch-like protein 2; WNK kinase