Mechanism of cell death induction by the failure of ribosome-associated quality control pathway

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K06615
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 44010:Cell biology-related
• Research Institution: Nagoya City University (2022); Tohoku University (2020-2021)
• Principal Investigator: Udagawa Tsuyoshi 名古屋市立大学, 医薬学総合研究院(薬学), 准教授 (20644199)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 翻訳 / 品質管理 / リボソーム / タンパク質凝集体 / タンパク質分解 / 神経変性

Outline of Final Research Achievements

In this study we aimed to elucidate the mechanism of nascent protein degradation and cell death induction by the execution and the failure of ribosome-associated quality control, RQC, pathway which targets the stalled ribosomes on the aberrant mRNAs. Especially we focused on identifying the peptide tag, called CAT-tail, added to the C-terminal end of the aberrant nascent peptides and elucidated its impact on the nascent peptide degradation and its potential toxic effect when accumulated in mammalian cells. We found that mammalian CAT-tails were mainly composed of alanine with several other amino acids including glycine and threonine and alanine-tailing promoted the degradation of the tailed proteins when they are expressed at a relatively low level, but formed protein aggregates and induced apoptotic cell death when expressed at high level or upon the failure of RQC.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

近年、新生タンパク質の品質管理がタンパク質恒常性の維持に重要な役割を果たし、その異常が神経・精神疾患、がん、生活習慣病などさまざまなヒト疾患にも関わることが示唆されている。本研究では異常な翻訳停滞によって誘導される新生タンパク質分解機構RQC（ribosome-associated quality control）に注目し、神経変性疾患の原因となりうることが報告されていた異常新生タンパク質の末端修飾（CATテイル）の同定とCATテイル化タンパク質の蓄積が細胞死を誘導する際の配列依存性を解明することに成功した。