A novel mechanism of endosome maturation

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K15786
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: Tohoku University
• Principal Investigator: Matsui Takahide 東北大学, 生命科学研究科, 助教 (10827794)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: endosome / lysosome

Outline of Final Research Achievements

Endosome maturation is essential for efficient degradation of internalized extracellular molecules and plasma membrane proteins. Two Rab GTPases, Rab5 and Rab7, are known to regulate endosome maturation, and a Rab5-to-Rab7 conversion mediated by a Rab7 activator, Mon1-Ccz1, is essential for progression of the maturation process. However, the importance and mechanism of Rab5 inactivation during endosome maturation is poorly understood. We showed that Rab5 hyperactivation in addition to Rab7 inactivation occurs in the absence of Mon1. We then identified TBC1D18 as a Rab5-GAP by comprehensive screening of TBC-domain-containing Rab-GAPs. Expression of TBC1D18 in Mon1-KO cells rescued the defects in endosome maturation, whereas its depletion attenuated endosome formation and degradation of endocytosed cargos. Moreover, TBC1D18 was found to be able to interact with Mon1. Thus, TBC1D18 is a crucial regulator of endosome maturation that functions together with Mon1.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

エンドソーム成熟はあらゆる真核細胞で保存された現象であり、細胞の恒常性維持に必須の機構である。実際にこの機構の破綻によりリソソーム病と総称される様々な疾患が引き起こされることが知られている。しかし、エンドソーム成熟の重要性が知られている一方で、その制御機構は未解明な点が多い。本研究では、新規のエンドソーム成熟制御因子としてTBC1D18を同定することに成功した。本研究をきっかけとして、TBC1D18の作用機序を明らかにすることで、エンドソーム成熟メカニズムの解明にとどまらず、リソソーム病の原因解明の一助となる可能性もある。