Roles of Pre-emptive pathway in the protein quality control.

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H03657
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Tokyo Metropolitan University
• Principal Investigator: Kawahara Hiroyuki 首都大学東京, 理学研究科, 教授 (70291151)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: preemptive pathway / BAG6 / Ubiquitin / Proteasome / Membrane protein / Protein degradation

Outline of Final Research Achievements

GDP-bound cytoplasmic forms of Rab proteins are prone to aggregation due to the exposure of hydrophobic groups but the machinery that determines the fate of Rab species in the cytosol has not been elucidated in detail. In this study, we find that BAG6 predominantly recognizes a cryptic portion of GDP-associated Rab8a, while its major GTP-bound active form is not recognized. The hydrophobic residues of the Switch I region of Rab8a are essential for its interaction with BAG6 and the degradation of GDP-Rab8a via the ubiquitin-proteasome system . BAG6 prevents the excess accumulation of inactive Rab8a, whose accumulation impairs intracellular membrane trafficking. From these observations, we suggest that Rab proteins represent a novel set of substrates for BAG6, and the BAG6-mediated pathway is associated with the regulation of membrane vesicle trafficking events in mammalian cells.

Free Research Field

細胞生物学・生化学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、研究代表者が世界に先駆けて見出した独創的、かつ先駆的な研究成果を発展的にふまえた研究展開の一環である。本研究により、プレエンプティヴ品質管理の破綻が引き起こす疾患発症の全く新しい原理解明に貢献できた。
本研究は、ユビキチン系の制御機構と相携える重要な研究であり、新合成タンパク質の動態制御の基礎研究から、不良膜タンパク質の異常凝集に起因する各種病態発症の分子機構解明へと新領域を開拓することが充分に見込まれる。本研究で得られた情報・基盤技術はどの多細胞生物にも応用可能で、知的資産の形成に資することと同時に、人類社会に与える革新的インパクトも極めて大きい。