Analysis of TORC1 regulation via PI3P turnover at sub-cellular lebel

• Project/Area Number: 16K07347
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cell biology
• Research Institution: Osaka University
• Principal Investigator: NODA Takeshi 大阪大学, 歯学研究科, 教授 (00290908)
• Research Collaborator: Araki Yasuhiro ; Hao Feike
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: TORC1 / グルタミン / Rheb / Pib2 / mTOR / オートファジー / PI3P

Outline of Final Research Achievements

TORC1 is a master regulator of cell growth and autophagy, and attracts much attention from the view of cancer progression and longevity. However its regulatory mechanism remain to be elucidated. In this study, 1)we have uncovered that Rheb is localized at Golgi body and activates TORC1 localized at the lysosome via newly identified Golgi lysosome contact site. 2)A complex containing yeast Pib2 protein can directly binds to glutamine, by which TORC1 is activated.

Academic Significance and Societal Importance of the Research Achievements

TORC1は細胞成長の中心的な制御因子であり、がんや免疫をはじめ、多くの疾病に深く関与することより、多くの関心が寄せられている。今回、主に２つのTORC1の制御機構を明らかにすることに成功した。本研究に基づき、TORC1の制御機構についての理解が進展したことと同時に、将来的にTORC1関連疾病を克服することを目指した、創薬等の研究においての分子標的因子を新たに提案することができた。

Research Products

• [Journal Article] Gtr/Ego-independent TORC1 activation is achieved through a glutamine-sensitive interaction with Pib2 on the vacuolar membrane (2018)
  • Author(s): Ukai Hirofumi、Araki Yasuhiro、Kira Shintaro、Oikawa Yu、May Alexander I.、Noda Takeshi
  • Journal Title: PLOS Genetics Volume: 14 Issue: 4 Pages: e1007334-e1007334
  • DOI: 10.1371/journal.pgen.1007334
  • Peer Reviewed / Open Access
• [Journal Article] Rheb localized on the Golgi membrane activates lysosome-localized mTORC1 at the Golgi lysosome contact site (2018)
  • Author(s): Feike Hao, Kazuhiko Kondo, Takashi Itoh, Sumiko Ikari, Shigeyuki Nada, Masato Okada, Takeshi Noda
  • Journal Title: J cell Science Volume: 131 Issue: 3 Pages: 208017-208017
  • DOI: 10.1242/jcs.208017
  • Peer Reviewed / Open Access
• [Journal Article] Gtr/Ego-independent TORC1 activation is achieved through a glutamine-sensitive interaction with Pib2 on the vacuolar membrane. (2018)
  • Author(s): 3.Ukai, H., Araki, Y., Kira, S., Oikawa, Y., May, A. I., and Noda, T
  • Journal Title: PLOS gengetics Volume: in press
  • Peer Reviewed
• [Journal Article] The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity. (2016)
  • Author(s): Hao F, Itoh T, Morita E, Shirahama-Noda K, Yoshimori T, Noda T.
  • Journal Title: FEBS Lett. Volume: 509 Issue: 1 Pages: 161-173
  • DOI: 10.1002/1873-3468.12048
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] TORC1 活性の空間的制御 (2018)
  • Author(s): 野田健司
  • Organizer: 第９１回日本生化学会大会
  • Invited
• [Presentation] Rheb is localized on Golgi and activates mTORC1 at the Golgi lysosome contact site (2017)
  • Author(s): Hao F, Kondo K, Itoh T, Nada S, Okada M, and Noda T
  • Organizer: The 8th International Symposium on Autophagy
  • Int'l Joint Research
• [Presentation] Amino acids activate TORC1 via Pib2 and Gtr dependent pathways to regulate autophagy (2017)
  • Author(s): Ukai H, Araki Y, Kira S, Noda T
  • Organizer: The 8th International Symposium on Autophagy
  • Int'l Joint Research
• [Presentation] The PtdIns3-phosphatase MTMR3 interacts with mTORC1 and suppresses its activity (2016)
  • Author(s): Feike Hao、伊藤 敬、森田 英嗣、野田 佳苗、吉森 保、野田 健司
  • Organizer: 第６８回日本細胞生物学会大会
  • Place of Presentation: 京都テルサ（京都府京都市）