| Project/Area Number |
17K07295
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Molecular biology
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| Research Institution | Institute for Developmental Research Aichi Developmental Disability Center |
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Principal Investigator |
Kawaguchi Yoshiharu 愛知県医療療育総合センター発達障害研究所, 細胞病態研究部, 主任研究員 (00450833)
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| Project Period (FY) |
2017-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | アセチル化 / TSC2 / ｍTOR / 翻訳後修飾 / mTOR / 線維性硬化症 / 自閉症 / 概日リズム / Rheb / SIRT1 / 脱アセチル化 / 可逆的アセチル化 / タンパク質の翻訳後修飾 |
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| Outline of Final Research Achievements |
Protein acetylation, a post transcriptional modification, is known to control protein function. We found a novel acetylation site on Tuberous sclerosis complex 2 (TSC2), and that this acetylation regulates TSC2 activity, which in turn controls mTOR signaling. Mechanistically, acetylation reduced Akt-mediated phosphorylation (Thr1462) and increased the ability of TSC2 to sequester an mTOR-activating GTPase, Rheb, thereby preventing mTOR activation. Moreover, we found that acetylation status of TSC2 changes with circadian rhythm. Our study suggests a mechanism whereby reversible acetylation regulates TSC2 activity to modulate mTOR activation, and provides a new therapeutic target for mTOR-mediated diseases.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究は、タンパク質のアセチル化がヒストンによる遺伝子発現調節以外にも重要な役割を担うことを示す重要な成果である。また、TSC２分子がｍTORシグナリングの調節因子であることから、アセチル化によるTSC2分子の機能調節の発見はｍTORの機能障害が関与する様々な疾患の病態解明や新規治療法の開発に貢献する。
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