| Project/Area Number |
18K06112
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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 | Kobe 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 |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 小胞体 / 膜変形タンパク質 / オートファジー / ER-phagy / three-way junction / TMCC3 / 脂肪酸伸長サイクル / カルシウムポンプ / Three-way junction / 小胞体膜タンパク質 / 膜挿入 |
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| Outline of Final Research Achievements |
Homeostasis of the endoplasmic reticulum (ER) is maintained through selective autophagy termed ER-phagy. ER-phagy is the process in which isolation membranes sequester portions of the ER membrane and deform them into vesicles, resulting in formation of autophagosomes toward turnover of the ER components. Therefore, proteostasis of ER membrane-shaping proteins would be expected to be crucial for the ER homeostasis. In this study, we identified TMCC3 as an ER membrane protein localizing at three-way junctions, the ER subdomains where ER-phagy regulators are concentrated. We revealed that TMCC3 bound to the ER membrane-shaping proteins and regulated formation of the three-way junctions. We found an amino acid sequence that facilitated incorporation of ER membrane proteins into autophagosomes. Besides, we revealed that the fatty acid elongation cycle in the ER membrane, which is involved in homeostasis of the ER membrane, physically associated with the ER calcium pump.
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| Academic Significance and Societal Importance of the Research Achievements |
膜変形タンパク質とER-phagyの異常は遺伝性痙性対麻痺と遺伝性感覚性自律神経性ニューロパチーをそれぞれ引き起こす。本研究で発見したTMCC3は膜変形タンパク質に結合し、ER-phagyに重要な小胞体の膜形態を制御する。従って、TMCC3を起点とする膜変形タンパク質のプロテオスタシス異常という視点からこれらの神経疾患の発症機序の理解に繋がる可能性がある。また、カルシウムポンプの異常は遺伝性角化症であるダリエー病を引き起こす。本研究により、ダリエー病が脂肪酸伸長サイクルを介した小胞体膜の恒常性異常と関係する可能性がある。このように本研究成果は学術的にも社会的にも意義が大きいと考えている。
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