Analysis of nuclear membrane stress production mechanism associated with the regulation of nuclear membrane lipid metabolism

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06173
• 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: Hokkaido University (2022-2023); Microbial Chemistry Research Foundation (2021)
• Principal Investigator: Ogasawara Yuta 北海道大学, 遺伝子病制御研究所, 特任助教 (00773524)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 核膜ストレス / オートファジー / 脂質代謝

Outline of Final Research Achievements

In this study, we found that the deficiency of CCTβ in osteosarcoma cells U2OS leads to significant changes in nuclear membrane morphology. Additionally, we elucidated that several Atgs involved in mammalian autophagy, such as DFCP1, Atg13, and WIPI2, form droplet-like structures during autophagosome formation using live-imaging and FRAP methods. It was suggested that human Atg13 and WIPI2, which possess intrinsically disordered regions, contribute to the higher-order structure formation of Atgs through liquid-liquid phase separation. It was also suggested that the liquid-liquid phase separation of Atg13 and WIPI2 near sites of nuclear membrane stress enables a rapid stress response via autophagy.

Free Research Field

細胞生物

Academic Significance and Societal Importance of the Research Achievements

これまでに出芽酵母の液胞膜上の特定部位においてAtgの液滴構造(Fujioka et al. Nature. 2020)が形成されることについては既に報告されていたが、哺乳類ではいまだ報告がなく本研究で見いだされた相分離を介したオートファゴソーム形成機構は新規のメカニズムである。癌遺伝子RASの活性化がnucleophagyを介した核膜構成成分の分解を誘導することで、核膜ストレスの発生および細胞老化を引き起こすことが報告されているが、Atg13やWIPI2の相分離を制御することでオートファジーによる核膜ストレスの制御が可能となり老化の予防も期待できると考えている。