The elucidation of the protein degradation system controlling TORC1, which governs growth and proliferation.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K06170
• 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: Osaka University
• Principal Investigator: Araki Yasuhiro 大阪大学, 大学院歯学研究科, 助教 (60345254)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 栄養感知 / 細胞成長 / 増殖 / 酵母 / アミノ酸 / TORC1

Outline of Final Research Achievements

TORC1 is a master regulator that monitors the availability of various amino acids to promote cell growth in Saccharomyces cerevisiae. It is activated via two distinct upstream pathways, the Gtr pathway, which corresponds to mammalian Rag, and the Pib2 pathway. This study showed that Ser3 was phosphorylated exclusively in a Pib2-dependent manner. Using Ser3 as an indicator of TORC1 activity, together with the established TORC1 substrate Sch9, we investigated which pathways were employed by individual amino acids. Different amino acids exhibited different dependencies on the Gtr and Pib2 pathways. Cysteine was most dependent on the Pib2 pathway, and increased the interaction between TORC1 and Pib2 in vivo and in vitro. Moreover, cysteine directly bound to Pib2 via W632 and F635, two critical residues in the T(ail) motif that are necessary to activate TORC1. These results indicate that Pib2 functions as a sensor for cysteine in TORC1 regulation.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

TORC1阻害剤であるラパマイシンは様々な薬理作用を有し、TORC1の応用研究も熾烈を極めている。哺乳類細胞においてもGtr/Ego経路以外にTORC1活性化経路の存在が示唆されているが分子的実体は不明である。TORC1関連因子は進化上高度に保存されており、Pib2経路及び制御機構も進化上保存されていると想定される。アミノ酸センサーは哺乳細胞において少数のアミノ酸について先駆的研究がなされているが、これらは種間で保存されておらず、酵母においてアミノ酸センサーの知見は皆無であった。本研究により、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理解が種を超えて大きく進むものと考える。