Cell Biology of Proteasomes
| Project/Area Number |
19H00997
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Medium-sized Section 44:Biology at cellular to organismal levels, and related fields
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| Research Institution | Tokyo Metropolitan Institute of Medical Science |
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Principal Investigator |
TANAKA Keiji 公益財団法人東京都医学総合研究所, 基礎医科学研究分野, 理事長 (10108871)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥45,630,000 (Direct Cost: ¥35,100,000、Indirect Cost: ¥10,530,000)
Fiscal Year 2021: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
Fiscal Year 2020: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
Fiscal Year 2019: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000)
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| Keywords | プロテアソーム / ユビキチン / 細胞内タンパク質分解 / 液―液相分離 / 神経変性疾患 / 遺伝学的解析 / ストレス応答 / PROTACs / ATP / 液一液相分離 / タンパク質分解 / プロテアソーム顆粒 / 液ー液相分離 / RAD23B / 液滴 / メンブレンレスオルガネラ / 液-液相分離 / オートファジー / 品質管理 |
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| Outline of Research at the Start |
代表者はATP依存性のタンパク質分解装置であるプロテアソームの構造と機能の解明を目指した研究を包括的に推進、分子基盤の確立や動作原理などを明らかにしてきた。しかしプロテアソームの生理学においてはまだ未解決の課題が山積している。本課題では、プロテアソームの細胞生理学的理解を深めるために、複数の遺伝子改変動物を作出して、個体レベルでのプロテアソームの動態や機能の解析を目指す。加えてごく最近、代表者らが見出した「ストレスに応答して細胞質や核に生じる特殊なプロテアソーム顆粒」を詳細に解析する。本研究は、代表者のライフワークの集大成であり、プロテアソームの生理機能解明に向けて新たな領域の開拓を目指す。
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| Outline of Final Research Achievements |
In the selective proteolytic pathway by proteasomes, there are many unresolved issues, such as the use of higher-order structural information of ubiquitin modifications presented to target proteins (referred as ubiquitin code) and their discriminating molecules (referred as decoders), as well as the action and regulatory mechanisms of proteasomes. In this study, we aimed to elucidate the pathology and physiology of the proteasome at in vivo level by creating mice with functionally weak activity of proteasomes and to provide a molecular basis for proteasome drug discovery. We successfully established a new concept of liquid-liquid phase separation-dependent proteolysis mechanism responsible for environmental stresses. Moreover, we have also clarified the involvement of ubiquitin-branched chains and identification of their generating enzymes in the selective proteolysis inducer PROTACs, opening a new possibility for next-generation drug discovery research.
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| Academic Significance and Societal Importance of the Research Achievements |
近年、タンパク質分解の細胞内機構と病態生理研究は飛躍的に進展しつつあり、本研究では、その中核酵素であるプロテアソームの基礎研究から病態解明及び創薬研究への道を開拓した。プロテアソームの変異疾患が相次いで報告されているが、それらを検証するための機能減弱マウスの作出に世界で初めて成功した。またプロテアソームが環境ストレスに応答して可逆的に相分離しタンパク質の迅速分解に貢献していることの発見は、神経変性疾患における易凝集性タンパク質の異常による封入体形成機序解明のヒントになる。標的タンパク質分解誘導剤PROTACsにおけるユビキチン分岐鎖と創成酵素の発見は、次世代創薬研究への波及効果が期待できる。
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Report
(5 results)
Research Products
(43 results)
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[Journal Article] Mammalian BCAS3 and C16orf70 associate with the autophagosome formation site in response to selective and non-selective autophagy2021
Author(s)
Kojima, K., Yamano, K., Kosako, H., Imai, K., Kikuchi, R., Tanaka, K., and Matsuda, M.
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Journal Title
Autophagy
Volume: 17
Pages: 2011-2036
Related Report
Peer Reviewed / Open Access
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[Journal Article] Unfolding is the driving force for mitochondrial import and degradation of the Parkinson's disease-related protein DJ-12021
Author(s)
Queliconi BB, Kojima W, Kimura M, Imai K, Udagawa C, Motono C, Hirokawa T, Tashiro S, Caaveiro JMM, Tsumoto K, Yamano K, Tanaka K, Matsuda N
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Journal Title
J Cell Sci
Volume: 134
Issue: 22
Pages: 1-1
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation2020
Author(s)
A. Nishiyama, C. Mulholland, S. Bultmann, S. Kori, A. Endo, Y. Saeki, W. Qin, C. Trummer, Y. Chiba, H. Yokoyama, S. Kumamoto, T. Kawakami, H. Hojo, G. Nagae, H. Aburatani, K. Tanaka, K. Arita, H. Leonhardt, M. Nakanishi
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Journal Title
Nat. Commun.
Volume: 11
Issue: 1
Pages: 1222-1222
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Molecular bases for HOIPINs-mediated inhibition of LUBAC and innate immune responses.2020
Author(s)
Oikawa D, Sato Y, Ohtake F, Komakura K, Hanada K, Sugawara K, Terawaki S, Mizukami Y, Phuong HT, Iio K, Obika S, Fukushi M, Irie T, Tsuruta D, Sakamoto S, Tanaka K, Saeki Y, Fukai S, Tokunaga F.
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Journal Title
Commun. Biol.
Volume: 3
Issue: 1
Pages: 163-163
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Trans-omics impact of thymoproteasome in cortical thymic epithelial cells.2019
Author(s)
Ohigashi I, Tanaka Y, Kondo K, Fujimori S, Kondo H, Palin A, Hoffmann V, Kozai M, Matsushita Y, Uda S, Motosugi R, Hamazaki J, Kubota H, Murata S, Tanaka K, Katagiri T, Kosako H, Takahama Y
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Journal Title
Cell Reports
Volume: 29
Issue: 9
Pages: 2901-2916
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Book] 実験医学2020
Author(s)
田中啓二、若槻壮市
Total Pages
240
Publisher
羊土社
Related Report
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