Regulation of biological processes by stress granule formation and its failure in human diseases

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02609
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48040:Medical biochemistry-related
• Research Institution: The University of Tokyo
• Principal Investigator: Takekawa Mutsuhiro 東京大学, 医科学研究所, 教授 (30322332)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ストレス顆粒 / 液液相分離 / がん / プロテオミクス

Outline of Final Research Achievements

Stress granules (SGs) are cytoplasmic ribonucleoprotein foci that appear when eukaryotic cells are exposed to specific types of stresses such as ER stress, heat shock, hypoxia, and viral infection. The core components of SGs are large aggregates of stalled translation pre-initiation complexes that contain mRNA, 40S ribosomal subunits, translation initiation factors and several RNA-binding proteins (RBPs). To understand the role of SG formation in regulation of biological stress response, we developed a strategy to identify the molecules that can localize in SGs, and identified novel SG-component proteins such as nucleotide-binding proteins, cytoskeletal proteins, and signaling molecules. By analyzing some of these SG-component proteins, we elucidated the molecular mechanism as to how SG assembly regulates stress-induced apoptosis and immune-response. We also uncovered a novel role of SG formation in tumorigenesis.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

近年、SGの形成異常が、癌、神経変性疾患、ウイルス感染症等の病態に深く関与することが見出され、注目を集めている。しかしながら、SGの形成機構やその構成分子の詳細は未だ不明である。本研究によって、新たなSG構成分子が多数同定されるとともに、SG形成機構の一端が明らかとなった。また、SG形成による細胞死・免疫応答制御機構を分子レベルで解き明かすことが出来た。さらにSGと癌病態との関連についても解析を進め、腫瘍組織内におけるSGの形成異常が、癌細胞の抗癌剤抵抗性獲得や癌の進展に寄与することを明らかにした。これらの知見を活用することで、癌などの疾病に対する新たな診断・治療法開発への応用が期待される。