Elucidation of novel functions of VCP, a major ATPase in the cell

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03435
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Kyoto University
• Principal Investigator: KAKIZUKA Akira 京都大学, 生命科学研究科, 教授 (80204329)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: VCP / 飢餓 / 前立腺癌 / フェロトーシス / 生体応答

Outline of Final Research Achievements

Organisms respond to environmental changes and maintain homeostasis in them. Starvation is a representative of the environmental changes we encounter on a daily basis. We have assumed that VCP, the most abundant soluble ATPase in cells, is a key molecule that controls intracellular energy production and consumption. In this study, we showed that there is a previously unknown mechanism that protects cells from starvation: when PC3 and other prostate cancer cells are starved, VCP senses a decrease in glutamine and changes its localization to aggregate-like structures, thereby reducing the amount of free VCP, then suppressing mitochondrial activities, and inhibiting ROS production, and the resulting ferroptosis (cell death). In addition, we found that KUS121, a compound that specifically inhibits the ATPase activity of VCP, can dramatically improve the pathological conditions of renal reperfusion models and traumatic knee arthropathy models.

Free Research Field

分子病態学、創薬

Academic Significance and Societal Importance of the Research Achievements

生物の生存にとって最大の脅威の1つが飢餓であるが、飢餓に対して生物がどのような対応を行っているかはよく解っていなかった。本研究によって、細胞内でエネルギー代謝を制御する鍵分子であるVCPと呼ばれる主要なATPaseが、飢餓時に細胞内で凝集体様の構造物に局在を変化させることで、フェロトーシスとよばれる急激な細胞死を回避するメカニズムが存在することを明らかにした。一方、急性の腎傷害、膝関節症モデルに対し、このVCPのATPase活性を特異的に抑制する薬剤(KUS121)の投与が、有効な治療に繋がる可能性を動物実験で示すことができた。