ケモテクノロジーを利用したタンパク質分解制御

	研究代表者　村田 茂穂 東京大学大学院薬学系研究科蛋白質代謝学教室　教授
	研究分担者　山野 晃史 東京医科歯科大学　難治疾患研究所　機能分子病態学分野　准教授

本計画研究の概要

プロテアソームとオートファジーは真核細胞内の主たる分解系であり、生命活動を支えるタンパク質・オルガネラの動的な新陳代謝の中心を担っています。プロテアソームによるタンパク質分解は、高い基質選択性を持ったタンパク質分解であり、様々な生命活動の制御に必須の働きを担っています。オートファジーは、タンパク質凝集体や細胞内オルガネラを隔離膜で取り囲み、リソソームと融合させることによりその内容物を選択的かつ大規模に分解する系です。いずれの分解系においても、その分解するターゲットの選択にユビキチン修飾とその受容体分子が重要な役割を果たしています。これまで、遺伝子改変や発現制御などの手法によりこれら分解系の分子機構と生理機能の解明が進められてきましたが、制御に関与する分子の多くが細胞の生存に必須であり、分解系以外での機能も有しているなどのため、多くの問題が未解明のまま残されていました。本研究ではユビキチンの主たる役割の一つであるタンパク質分解・オルガネラ分解に焦点を当て、細胞内二大分解系であるプロテアソームとオートファジーによる分解過程において、特定のタンパク質間相互作用をタイムリーに喪失させることが可能な化合物や膜透過性ペプチドを利用し、遺伝子改変や発現制御実験では解決できなかった、基質選択性や分解系制御機構の新たな理解の解明を目指します。さらにその成果を活かして、プロテアソーム・オートファジー分解系と分解標的タンパク質・オルガネラを直接連結させるキメラ化合物を作出し、ユビキチン化を介さず直接的かつ選択的にタンパク質を分解誘導する方法論の確立を目指します。

研究概要を示す模式図

本領域での研究成果

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   プレスリリース
10. Arata Y, Watanabe A, Motosugi R, Murakami R, Goto T, Hori S, Hirayama S, Hamazaki J, Murata S.
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    PMID: 31621149
11. Yasuda S, Tsuchiya H, Kaiho A, Guo Q, Ikeuchi K, Endo A, Arai N, Ohtake F, Murata S, Inada T, Baumeister W, Fernández-Busnadiego R, Tanaka K, *Saeki Y.
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    プレスリリース
    http://www.igakuken.or.jp/topics/2020/0205.html （都医学研）
    https://www.amed.go.jp/news/release_20200206-02.html（AMED）
    Highlighted in Cell Res
    EurekAlert!
    Faculty Opinions
12. Waku T, Nakamura N, Koji M, Watanabe H, Katoh H, Tatsumi C, Tamura N, Hatanaka A, Hirose S, Katayama H, Tani M, Kubo Y, Hamazaki J, Hamakubo T, Watanabe A, Murata S, Kobayashi A.
    NRF3-POMP-20S Proteasome Assembly Axis Promotes Cancer Development via Ubiquitin-Independent Proteolysis of p53 and Retinoblastoma Protein.
    Mol. Cell. Biol. 40, e597-19 (2020)
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13. *Yamano K, Kikuchi R, Kojima W, Hayashida R, Koyano F, Kawawaki J, Shoda T, Demizu Y, Naito M, Tanaka K, *Matsuda N.
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14. Hashimoto E, Okuno S, Hirayama S, Arata Y, Goto T, Kosako H, Hamazaki J, *Murata S.
    Enhanced O-GlcNAcylation mediates cytoprotection under proteasome impairment by promoting proteasome turnover in cancer cells.
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15. Kojima W, *Yamano K, Kosako H, Imai K, Kikuchi R, Tanaka K, Matsuda N.
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16. Takehara Y, Yashiroda H, Matsuo Y, Zhao X, Kamigaki A, Matsuzaki T, Kosako H, Inada T, *Murata S.
    The ubiquitination-deubiquitination cycle on the ribosomal protein eS7A is crucial for efficient translation.
    iScience 24, 102145 (2021)
    PMID: 33665564
17. *Kanazawa N, Hemmi H, Kinjo N, Ohnishi H, Hamazaki J, Mishima H, Kinoshita A, Mizushima T, Hamada S, Hamada K, Kawamoto N, Kadowaki S, Honda Y, Izawa K, Nishikomori R, Tsumura M, Yamashita Y, Tamura S, Orimo T, Ozasa T, Kato T, Sasaki I, Fukuda-Ohta Y, Wakaki-Nishiyama N, Inaba Y, Kunimoto K, Okada S, Taketani T, Nakanishi K, Murata S, Yoshiura K, *Kaisho T.
    Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency.
    Nature Comm. 12, 6819 (2021)
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18. Watanabe A, Hama K, Watanabe K, Fujiwara Y, Yokoyama K, Murata S, *Takita R.
    Controlled tetradeuteration of straight-chain fatty acids: synthesis, application, and insight into the metabolism of oxidized linoleic acid.
    Angew Chem Int Ed Engl. e202202779 (2022)
    PMID: 35411582
19. *Tanahashi N, Komiyama M, Tanaka M, Yokobori Y, Murata S, Tanaka K.
    The effect of nutrient deprivation on proteasome activity in 4-week-old mice and 24-week-old mice.
    J Nutr Biochem 105, 108993 (2022)
    PMID: 35331898
20. Hayashida R, Kikuchi R, Imai K, Kojima W, Yamada T, Iijima M, Sesaki H, Tanaka K, *Matsuda N, *Yamano K.
    Elucidation of ubiquitin-conjugating enzymes that interact with RBR-type ubiquitin ligases using a liquid-liquid phase separation-based method.
    J Biol Chem. 299, 102822 (2023)
    PMID: 36563856

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4. Sasaki K, Takada K, Ohte Y, Kondo H, Sorimachi H, Tanaka K, *Takahama Y, *Murata S.
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   Nat. Commun. 6, 7484 (2015)
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5. Yamano K, Matsuda N, Tanaka K.
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9. Uechi H, Kuranaga E, Iriki T, Takano K, Hirayama S, Miura M, Hamazaki J, *Murata S.
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    PMID: 30104634