Novel regulatory mechanisms of stress-responsive signaling through liquid-liquid phase separation triggered by various molecular modifications

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02620
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Tohoku University
• Principal Investigator: Matsuzawa Atsushi 東北大学, 薬学研究科, 教授 (80345256)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: ストレス応答 / 翻訳後修飾 / 液－液相分離 / シグナル伝達 / 液滴

Outline of Final Research Achievements

Living organisms and cells maintain homeostasis by inducing appropriate responses through the control of various post-translational modifications of stress-responsive signaling molecules, depending on the type and strength of stress. In this study, we demonstrated that droplet-like structures formed by liquid-liquid phase separation are the starting points for inducing stress responses such as cell death and inflammation, contributing to the onset of diseases, and clarified the control mechanism of the formation of droplet-like structures through various molecular modifications according to the type and amount of stress. Furthermore, the inhibition of the formation of droplet-like structures actually suppressed cell death associated with neurodegenerative diseases, demonstrating that the unique droplet-like structures formed by stress are important as new drug discovery therapeutic targets for diseases, such as neurodegenerative diseases and cancer.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

近年発見された新しいタイプの細胞死は、神経変性疾患や癌等の様々な病態との関連が報告されており、新規創薬ターゲットとして注目されている。これらの誘導や制御の仕組みを解明することが、これらの疾患の新たな治療戦略開発に繋がる。本研究では、液－液相分離で形成される液滴様構造体が、細胞死等のストレス応答の誘導に不可欠であり、その液滴中の構成因子であるシグナル分子等に対する、ストレスの種類・量に応じた、ユビキチン化やリン酸化等の様々な翻訳後修飾が、液滴形成や細胞死の制御に重要であることが判明した。これらのシグナル分子や翻訳後修飾酵素を標的として、今後、画期的な疾患治療戦略や創薬開発が可能となる。