| Project/Area Number |
18K06129
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 43030:Functional biochemistry-related
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| Research Institution | Niigata University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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| Keywords | ミトコンドリア / オートファジー / マイトファジー / 酵母 / Atg32 / Ppg1 / Far複合体 / STRIPAK複合体 |
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| Outline of Final Research Achievements |
Mitophagy plays an important role in mitochondrial homeostasis. In yeast, the phosphorylation of the mitophagy receptor Atg32 by CK2 is essential for mitophagy. This phosphorylation is counteracted by the STRIPAK complex consisting of protein phosphatase Ppg1 and Far3-7-8-9-10-11, but the underlying mechanism remains elusive. Here we show that two subpopulations of the Far complex reside in the mitochondria and ER, respectively, and play distinct roles; the former inhibits mitophagy via Atg32 dephosphorylation, and the latter regulates TORC2 signaling. Ppg1 and Far11 form a subcomplex, and Ppg1 activity is required for the assembling integrity of Ppg1-Far11-Far8. The Far complex preferentially interacts with phosphorylated Atg32, and this interaction is weakened by mitophagy induction. Furthermore, the artificial tethering of Far8 to Atg32 prevents mitophagy. Taken together, the Ppg1-mediated Far complex formation and its dissociation from Atg32 are crucial for mitophagy regulation.
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| Academic Significance and Societal Importance of the Research Achievements |
マイトファジーを含むオルガネラの選択的分解機構は、レセプタータンパク質のリン酸化制御が重要であることが明らかになりつつあるが、関連キナーゼやホスファターゼが未同定であることが多く、詳細な制御機構は不明な点が多い。本研究では、酵母のマイトファジーレセプターであるAtg32の詳細なリン酸化制御機構を解明し、この研究分野を大きく前進させる成果を得た。また、Ppg1-Far複合体は、哺乳類ではSTRIPAK複合体として知られており、その機能不全は癌や糖尿病など様々な疾患を引き起こす。本研究で得たPpg1-Far複合体に関する知見は、STRIPAK複合体の関連疾患治療の糸口となる可能性を秘めている。
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