Regulation of mTORC1 and autophagy by the lysosomal amino acid transporter Spns1

• Project/Area Number: 17K07380
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cell biology
• Research Institution: Niigata University
• Principal Investigator: Katsuragi Yoshinori 新潟大学, 医歯学系, 助教 (60401759)
• Co-Investigator(Kenkyū-buntansha): 永森 收志 奈良県立医科大学, 医学部, 教授 (90467572)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: オートファジー / トランスポーター / p62 / Spns1 / マウス / リソソーム / 細胞・組織 / 蛋白質 / 遺伝子 / 脳・神経 / 癌

Outline of Final Research Achievements

① The mechanism of supplying the product obtained by autophagy to the cytoplasm is not well understood. We have found that Spns1 is involved in this role as below. (1) Spns1 is localized in the lysosomal membrane and is required for reactivation of mTORC1 during autophagy recovery. (2) liver-specific Spns1-KO mice showed liver inflammation and liver hypertrophy, and p62-accumulated autolysosome-like structures, which is characteristic of abnormal autophagy. Furthermore, (3) we attempted to identify the transport substrate of Spns1, which was inferred from metabolome analysis of Spns1-cKO mice.
② We also reported that USP10 and G3BP1 are involved in the formation of ubiquitinated protein aggregates by p62 and are involved in several neurodegenerative diseases.

Academic Significance and Societal Importance of the Research Achievements

①細胞生物学的および実験動物病理的な結果から、Spns1がオートファジーに関与することを強く示唆する結果を示した。また、本研究で作成したSpns1KOマウスやfloxマウスは、有用な研究リソースとなりうる。
②USP10やp62がどのようにして神経変性疾患（パーキンソン病やアルツハイマー病）に関与するのかはまだよくわかっていない。USP10に注目しているのはほぼ当グループのみで、先行研究はない。さらにUSP10やp62などの働きに注目して研究を進めていきたい。

Research Products

• [Journal Article] USP10 is a critical factor for Tau-positive stress granule formation in neuronal cells (2019)
  • Author(s): Piatnitskaia S, Takahashi M, Kitaura H, Katsuragi Y, Kakihana T, Zhang L, Kakita A, Iwakura Y, Nawa H, Miura T, Ikeuchi T, Hara T, Fujii M
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 10591-10591
  • DOI: 10.1038/s41598-019-47033-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] G3BP1 inhibits ubiquitinated protein aggregations induced by p62 and USP10 (2019)
  • Author(s): Anisimov S, Takahashi M, Kakihana T, Katsuragi Y, Kitaura H, Zhang L, Kakita A, Fujii M.
  • Journal Title: Sci Rep Volume: 9(1) Issue: 1 Pages: 12896-12896
  • DOI: 10.1038/s41598-019-46237-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] USP10 Is a Driver of Ubiquitinated Protein Aggregation and Aggresome Formation to Inhibit Apoptosis. (2018)
  • Author(s): Takahashi M, Kitaura H, Kakita A, Kakihana T, Katsuragi Y, Nameta M, Zhang L, Iwakura Y, Nawa H, Higuchi M, Komatsu M, Fujii M.
  • Journal Title: iScience Volume: 30 Pages: 433-450
  • DOI: 10.1016/j.isci.2018.11.006
  • Peer Reviewed / Open Access
• [Remarks] パーキンソン病において神経病原性蛋白質を不活化する蛋白質を同定
  • URL: https://www.med.niigata-u.ac.jp/contents/info/news_topics/93_index.html