Towards a comprehensive understanding of the amino acid-sensing system that induces activation of TORC1 that controls cell growth

2021 Fiscal Year Final Research Report

• Project/Area Number: 18K06111
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: Osaka University
• Principal Investigator: Araki Yasuhiro 大阪大学, 歯学研究科, 助教 (60345254)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 酵母 / TORC1 / アミノ酸 / 細胞成長 / 栄養増殖 / リン酸化修飾

Outline of Final Research Achievements

The function of TORC1 as the critical regulator of growth and metabolism is universally conserved amongst eukaryotes. However, the identification of upstream and downstream factors of TORC1 for cell proliferation and growth remains to be investigated. A combination of biochemical and microscopic approaches demonstrated that an enzyme that catalyzes the first step of the serine synthesis pathway physically interacts with TORC1 and co-localizes with the TORC1 complex in vivo. We also found that TORC1 activity is required to maintain intracellular serine at levels sufficient for growth and that the enzyme is phosphorylated by TORC1 in a manner dependent on the Pib2 pathway. This study revealed that TORC1 directly controls an amino acid synthesis pathway in addition to other macromolecule syntheses.

Free Research Field

栄養源に依存した細胞応答とその制御機構

Academic Significance and Societal Importance of the Research Achievements

二つのTORC1活性化経路の上流に位置するアミノ酸の分類、経路特異的なTORC1の基質の単離といった本研究の成果は、TORC1活性化の分子機構、特に多様なアミノ酸センシング機構の解明の礎になると考える。またTORC1の特異的阻害剤であるラパマイシンは免疫抑制効果、抗がん剤効果、寿命延長効果などの薬理作用があり、様々な疾患の治療薬として用いられているがその副作用が問題となっている。将来的に、本研究はこれら生命現象のメカニズムの理解に留まらず、更なる精緻な治療法の開発の基盤となることが期待される。