Molecular mechanisms underlying the higher-order assembly of the ULK1 complex that senses autophagy-inducing signals
| Project/Area Number |
17H03670
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cell biology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Yamamoto Hayashi 東京大学, 大学院医学系研究科(医学部), 講師 (80551283)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
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| Keywords | オートファジー / ULK1複合体 / シグナル伝達 / 高次集積体 / 分子機構 / 液滴形成 / 始動複合体 / 相分離 / 液滴 / 選択的基質 / 局在化メカニズム / 哺乳類細胞 / phase separation / mTORC1 / 哺乳類 / mTORC / pahse separation |
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| Outline of Final Research Achievements |
Upon induction of autophagy, a double membrane-bound autophagosome is generated and fuses with lysosomes to degrade its contents. However, it remains unclear how the ULK1 complex receives the autophagy-inducing signals from the mTORC1 complex. In this study, we found that the intrinsically disordered region (IDR) of ULK1 directly interacts with the mTORC1 complex. In yeast, the TORC1-interacting region is the IDR of Atg13. Thus, our findings indicate that the signal recognition system is shifted from Atg13 to ULK1 during evolution. We also identified the regions of ULK1, ATG13, and FIP200 involved in the formation of the ULK1 complex and found that the ULK1 complex further assembles with each other to form liquid droplet-like structures in vivo. We also found that ATG9 vesicles are recruited via selective autophagy substrates in addition to the ATG13-dependent pathway found in yeast. We show that mammals have acquired a selective autophagy substrate-dependent pathway during evolution.
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| Academic Significance and Societal Importance of the Research Achievements |
哺乳類でのオートファジー誘導機構については具体的な分子機構が不明であったが、mTORC1複合体とULK1の相互作用領域を特定することで、シグナル伝達機構が進化の過程で大きく変化し、哺乳類ではより複雑化していることを明らかにした。この成果は、哺乳類オートファジー研究に新たな視点を提供するだけでなく、創薬ターゲットとしてのULK1の有用性を示すものとなる。ATG9ベシクルのリクルート機構として新たに見出した分解基質依存性経路は、細胞内品質管理に関わる選択的オートファジーの効率化、厳密化のために獲得した経路と考えられ、恒常性オートファジーや選択的オートファジーの制御に関わる新しい発見である。
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Report
(4 results)
Research Products
(8 results)
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[Journal Article] Evolution from covalent conjugation to non-covalent interaction in the ubiquitin-like ATG12 system2019
Author(s)
Pang, Y., Yamamoto, H., Sakamoto, H., Oku, M., Mutungi, J.K., Sahani, M.H., Kurikawa, Y., Kita, K., Noda, N.N., Sakai, Y., Jia, H., Mizushima, N.
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Journal Title
Nat. Struct. Mol. Biol.
Volume: 26
Issue: 4
Pages: 289-296
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Autophagosomal YKT6 is required for fusion with lysosomes independently of syntaxin 17.2018
Author(s)
Matsui, T., Jiang, P., Nakano, S., Sakamaki, Y., Yamamoto, H., and Mizushima, N.
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Journal Title
J. Cell Biol.
Volume: 217
Issue: 8
Pages: 2633-2645
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Evolution from covalent conjugation to non-covalent interaction in the ubiquitin-like ATG12 system2019
Author(s)
Yamamoto, H., Pang, Y., Sakamoto, H., Oku, M., Yazaki, E., Sakai, Y., Jia, H., Mizushima, N.
Organizer
The 9th International Symposium on Autophagy
Related Report
Int'l Joint Research
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