The mechanistic insight into the ribosome splitting event to initiate the RQC pathway

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K06481
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43010:Molecular biology-related
• Research Institution: The University of Tokyo (2021); Tohoku University (2019-2020)
• Principal Investigator: Matsuo Yoshitaka 東京大学, 医科学研究所, 准教授 (00725252)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: リボソーム / ユビキチン化 / 品質管理

Outline of Final Research Achievements

Ribosome-associated quality control (RQC) represents a rescue pathway in eukaryotic cells triggered upon translational stalling. However, the mechanism underlying the ubiquitin-dependent ribosome dissociation remain poorly understood.
In the project, we established the in vitro system, which enabled the reconstitution of Hel2-dependent poly-ubiquitination of collided tri-ribosomes. This system showed that the collided ribosome were efficiently recognized by Hel2 and ubiquitinated. Subsequently, the Slh1 helicase subunit of the RQC trigger (RQT) complex preferentially dissociates the first stalled poly-ubiquitinated ribosome in an ATP-dependent manner. Together, these findings provide fundamental mechanistic insights into RQC and its physiological role in maintaining cellular protein homeostasis.

Free Research Field

生化学・分子生物学

Academic Significance and Societal Importance of the Research Achievements

タンパク質の合成途中のエラーによる翻訳停止はタンパク質の機能の重大な欠陥を引き起こし、タンパク質の恒常性の破綻につながります。タンパク質の恒常性の破綻は、更に不良なタンパク質の蓄積やオルガネラの損傷、シグナル伝達経路の撹乱など、広範な細胞機能の障害を引き起こすため、アルツハイマー病やパーキンソン病などの神経変性疾患の原因になると考えられています。本研究では、細胞の持つ品質管理の仕組みを分子レベルで解明しました。本成果は、神経変性疾患の原因となる異常タンパク質の合成を効率的に抑制する治療薬の開発に貢献する事が期待されます。