Elucidation of molecular mechanism of proteinuria mediated by Cubilin

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K07872
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: The University of Tokyo
• Principal Investigator: Harita Yutaka 東京大学, 医学部附属病院, 准教授 (10451866)
• Co-Investigator(Kenkyū-buntansha): 神田 祥一郎 東京大学, 医学部附属病院, 講師 (60632651)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 蛋白尿 / 尿細管 / Cubilin / Amnionless / アルブミン

Outline of Final Research Achievements

Cubilin (CUBN) and amnionless (AMN), expressed in kidney and intestine, form a multiligand receptor complex called CUBAM that plays a crucial role in albumin absorption. Here, we describe a quantitative assay to evaluate albumin uptake by CUBAM using cells expressing full-length CUBN and elucidate the crucial roles of the C-terminal part of CUBN and the endocytosis signal motifs of AMN in albumin endocytosis. We also demonstrate that nuclear valosin-containing protein-like 2 (NVL2), an interacting protein of AMN, is involved in this process. Although NVL2 was mainly localized in the nucleolus in cells without AMN expression, it was translocated to the extranuclear compartment when coexpressed with AMN. NVL2 knockdown significantly impaired internalization of the CUBN-albumin complex in cultured cells, demonstrating an involvement of NVL2 in endocytic regulation. These findings uncover a link between membrane and nucleolar proteins that is involved in endocytic processes.

Free Research Field

小児科学

Academic Significance and Societal Importance of the Research Achievements

本研究により、尿細管における蛋白質の再吸収の新たな分子機序が明らかになった。蛋白尿は多くの腎疾患の発症進展において重要な役割を果たしており、そのメカニズムや治療標的を検討する上で重要な知見が得られた。