Pathophysiological roles of KLHL3-Cullin3 as a novel WNK regulatory system

2015 Fiscal Year Final Research Report

• Project/Area Number: 26860629
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Wakabayashi Mai 東京医科歯科大学, 医歯(薬)学総合研究科, 非常勤講師 (00707292)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: 高血圧症 / オートファジー / WNK / KLHL3 / PHAII / p62

Outline of Final Research Achievements

We reported that kelch-like protein 3 (KLHL3)-Cullin3 E3 ligase ubiquitinates with-no-lysine kinase 4 (WNK4) and that impaired WNK4 ubiquitination causes pseudohypoaldosteronism type II, a hereditary hypertensive disease. As proteasome inhibition is known to activate p62-mediated selective autophagy, we investigated whether WNK4 degradation induced by KLHL3 is also mediated by such an autophagic mechanism. 3-Methyladenine, an autophagy inhibitor, blocked the epoxomicin-induced decrease in WNK4. Co-immunoprecipitation assays revealed that KLHL3 formed a complex not only with WNK4 but also with p62. Under proteasome inhibition, p62 overexpression decreased KLHL3 and WNK4 protein levels, and p62 knockdown dramatically increased KLHL3 and WNK4 protein levels. Thus, WNK4 was degraded not only by proteasomes but also by p62-KLHL3-mediated selective autophagy, which may be involved in WNK regulation under certain pathophysiological conditions.

Free Research Field

高血圧症