Analysis for the functional roles of ezrin in the membrane trafficking

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K18240
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine; General physiology
• Research Institution: Chiba University (2018-2019); Ritsumeikan University (2017)
• Principal Investigator: Hatano Ryo 千葉大学, 大学院医学研究院, 助教 (60521713)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 足場タンパク質 / 細胞内トラフィッキング / トランスポーター / Fanconi症候群

Outline of Final Research Achievements

We have investigated the pathophysiological roles of ezrin, a cytoskeletal actin binding protein, in Dent’s disease, which is a disorder of proximal tubular solutes reabsorption. Ezrin is abundantly expressed in the proximal tubules and localizes the brush border membrane with several kinds of transporters. We previously reported that ezrin knockdown mice showed the hypophosphatemia and hyperphosphaturia due to mistargeting of phosphate transporters in the proximal tubules. In the present study, we newly identified that reabsorption of other solutes including amino acids, and low molecular weight protein, in the proximal tubules were also impaired. Abnormal subcellular localization of CLIC family proteins rather than CLC5, encoded by CLCN5 gene responsible for Dent's disease, is likely to be associated to the impaired membrane trafficking of multiple transporters in in the ezrin knockdown mice.

Free Research Field

腎臓生理学

Academic Significance and Societal Importance of the Research Achievements

本研究において、足場タンパク質エズリンが腎臓において溶質再吸収を調節するメカニズムの解明を試みた。エズリンを欠損する事によってDent病の様な腎臓での栄養再吸収障害が生じる事が判明した。尿細管におけるタンパク質の発現、局在解析から、必ずしもDent病の原因遺伝子であるClC-5の細胞内局在を直接制御するのではなく、CLICチャネルの局在を制御する事によって細胞内輸送を制御している事が示唆され、本研究成果はDent病を含む近位尿細管再吸収異常を伴う疾患の発症メカニズムの解明に寄与するものと考えられる。