Elucidation of regulatory mechanism of WNK signal by protein degradation system

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H05314
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: SOHARA Eisei 東京医科歯科大学, 大学院医歯学総合研究科, 准教授 (90510355)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: WNKキナーゼ / 塩分感受性高血圧 / 蛋白分解系

Outline of Final Research Achievements

Mutations in the with-no-lysine kinase 1 (WNK1), WNK4, kelch-like 3 (KLHL3), and cullin3 (CUL3) genes are known to cause the hereditary disease pseudohypoaldosteronism type II (PHAII). In this project, we generated Cul3 knock-in PHAII model mice and KLHL3-/- mice. KLHL3-/- mice showed PHAII-like phenotypes, whereas KLHL3+/- mice did not. We further demonstrated that the dimerization of KLHL3 can explain this dominant negative effect. We also found that KLHL3 expression was decreased in CUL3WT/Δex9 mice. These findings indicate that the decreased abundance of KLHL3 is a specific phenomenon caused by mutant CUL3 (Δexon9). In this study, we clarified WNK kinase degradation system by KLHL3 and Cullin3. We have also investigated the function of WNK kinase in the organ other than kidney, and found that WNK4 is an adipogenic factor and its deletion reduces diet-Induced obesity in mice.

Free Research Field

腎臓内科

Academic Significance and Societal Importance of the Research Achievements

本研究により、遺伝性高血圧疾患において新規に発見されたKLHL3とCullin3によるWNK分解系を転写からリン酸化蛋白修飾まで幅広い新規機序を明らかにすることができた。特に、KLHL2/3,Cullin3遺伝子改変マウスの作成により本制御系の破綻がもたらす病態を明らかにした。さらに研究を発展させ、遺伝子改変マウス等を駆使して様々な臓器や病態での新たなWNKシグナルの機能探求を明らかにし、WNKキナーゼの新規の基質や下流分子を同定しており、今後、臨床への発展も目指していきたい。