Elucidation of a novel homeostatic mechanism by enhanced O-GlcNAcylation under proteasome dysfunction

• Project/Area Number: 19K07062
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: The University of Tokyo
• Principal Investigator: Hamazaki Jun 東京大学, 大学院薬学系研究科(薬学部), 助教 (80533588)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: プロテアソーム / ユビキチン / O-GlcNAc / タンパク質分解

Outline of Research at the Start

近年になりタンパク質分解酵素複合体プロテアソームの阻害剤が難治性多発性骨髄腫の治療薬として使用されているが、薬剤耐性株に対する有効な対応策・治療戦略が確立していない。最近、申請者らはプロテアソーム不全時の恒常性維持にO-GlcNAc修飾タンパク質亢進が重要であることを見出した。本研究ではO-GlcNAc修飾タンパク質亢進による恒常性維持機構の分子メカニズム解明を軸にプロテアソーム不全に起因する病態発症機構の理解や、がん治療におけるプロテアソーム阻害剤耐性細胞に対する新たな分子標的薬ターゲット・治療アプローチの創出を目指す。

Outline of Final Research Achievements

The 26S proteasome is a protein complex that plays a role in protein degradation and plays an essential role in all eukaryotic cells. We identified that the enhanced O-GlcNAcylation of proteins is important to cellular proteostasis under proteasome dysfunction. In this study, we investigated the role and physiological importance of novel factors identified by mass spectrometry or genetic explorations to elucidate the molecular mechanism of O-GlcNAcylation. We identified the novel factor that act on the regulation of proteasome function and clarify their function of them, but there is a need for detailed verification and further development of research.

Academic Significance and Societal Importance of the Research Achievements

哺乳類プロテアソームの機能制御や生理機能についてはまだ未解明の部分が多く、プロテアソーム機能不全が関与すると考える広範な病態発症の基本原理の理解には課題が多いのが現状である。本研究においてプロテアソーム不全時にどのような細胞応答が生じるかを明らかにし、それを担う新たなプロテアソーム制御因子の同定と機能解明を進めたことは学術的にも重要性は高く、治療アプローチの作用点として今後研究が発展することで応用研究の基盤としても将来性が高い。

Research Products

• [Journal Article] Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency (2021)
  • Author(s): Kanazawa N, Hemmi H, Kinjo N, Ohnishi H, Hamazaki J, M.H, K.A, M.T, H.S, K.N, K.S, H.Y, I.K, N.R, T.M, Y.Y, T.S, O.T, O.T, K.T, S.I, F.Y, W.N, I.Y, K.K, O.S, T.T, N.K, M.S, Y.K, Kaisho T
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 0-0
  • DOI: 10.1038/s41467-021-27085-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recognition and degradation of ubiquitinated proteins by the 26S proteasome (2020)
  • Author(s): 濱崎 純、村田 茂穂
  • Journal Title: 生化学 Volume: 92 Issue: 1 Pages: 48-56
  • DOI: 10.14952/SEIKAGAKU.2020.920048
  • ISSN: 0037-1017
  • Year and Date: 2020-02-25
  • Peer Reviewed / Open Access
• [Journal Article] NRF3-POMP-20S proteasome assembly axis promotes cancer development via ubiquitin-independent proteolysis of p53 and Rb. (2020)
  • Author(s): 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
  • Journal Title: Molecular and Cellular Biology Volume: - Issue: 10 Pages: 1-1
  • DOI: 10.1128/mcb.00597-19
  • Peer Reviewed / Open Access
• [Journal Article] ER-Resident Transcription Factor Nrf1 Regulates Proteasome Expression and Beyond (2020)
  • Author(s): Hamazaki J, Murata S.
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 10 Pages: 3683-3683
  • DOI: 10.3390/ijms21103683
  • Peer Reviewed / Open Access
• [Journal Article] Enhanced O-GlcNAcylation Mediates Cytoprotection under Proteasome Impairment by Promoting Proteasome Turnover in Cancer Cells (2020)
  • Author(s): Hashimoto E, Okuno S, Hirayama S, Arata Y, Goto T, Kosako H, Hamazaki J, Murata S.
  • Journal Title: iScience Volume: 23 Issue: 7 Pages: 101299-101299
  • DOI: 10.1016/j.isci.2020.101299
  • NAID: 120007127449
  • Peer Reviewed / Open Access
• [Journal Article] Shigella effector IpaH4.5 targets 19S regulatory subunit RPN13 in the 26S proteasome to dampen cytotoxic T lymphocyte activation. (2019)
  • Author(s): Otsubo R, Mimura H, Ashida H, Hamazaki J, Murata S, Sasakawa C.
  • Journal Title: Cell Microbiol. Volume: 21 Issue: 3 Pages: e12974-e12974
  • DOI: 10.1111/cmi.12974
  • Peer Reviewed / Open Access
• [Journal Article] FAM48A mediates compensatory autophagy induced by proteasome impairment. (2019)
  • Author(s): Arata Y, Watanabe A, Motosugi R, Iemura SI, Natsume T, Mukai K, Taguchi T, Hirayama S, Hamazaki J, Murata S.
  • Journal Title: Genes Cells Volume: 24 Issue: 8 Pages: 559-568
  • DOI: 10.1111/gtc.12708
  • Peer Reviewed / Open Access
• [Journal Article] Defective induction of the proteasome associated with T-cell receptor signaling underlies T-cell senescence (2019)
  • Author(s): Arata Y, Watanabe A, Motosugi R, Murakami R, Goto T, Hori S, Hirayama S, Hamazaki J, Murata S.
  • Journal Title: Genes Cells Volume: 24 Issue: 12 Pages: 801-813
  • DOI: 10.1111/gtc.12728
  • Peer Reviewed
• [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
  • Journal Title: Cell Reports Volume: 29 Issue: 9 Pages: 2901-2916
  • DOI: 10.1016/j.celrep.2019.10.079
  • NAID: 120006894616
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ユビキチン・プロテアソーム系の不調による炎症性疾患発症の分子機構 (2022)
  • Author(s): 濱崎純、村田茂穂
  • Organizer: 第5回日本免疫不全・自己炎症学会 総会・学術集会
  • Invited
• [Presentation] プロテアソーム転写因子Nrf1活性化に働く新規プロテアーゼDDI2によるプロセシング条件の検討 (2021)
  • Author(s): 下岡雅和、濱崎純、村田茂穂
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] Senescence-associated nuclear proteasome foci degrade p21 and suppress mitochondrial activation (2021)
  • Author(s): 増田竣, 入木朋洋, 安田柊, 小迫英尊, 平山尚志郎, 大竹史明, 佐伯泰, 濱崎純, 村田茂穂
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] ユビキチンリガーゼRNF181はプロテアソーム機能低下時のプロテアソーム活性維持に重要な役割を果たす (2021)
  • Author(s): 吉敷純、平山尚志郎、小迫英尊、濱崎純、村田茂穂
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] 哺乳類プロテアソームの基礎的発現制御因子の探索 (2021)
  • Author(s): 山村まどか、本杉良、濱崎純、村田茂穂
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] 細胞老化依存的に生じるプロテアソームfociの機能解析 (2020)
  • Author(s): 安田柊、入木朋洋、増田竣、平山尚志郎、濱崎純、村田茂穂
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] The ubiquitin ligase RNF181 plays a pivotal role in sustaining the mammalian proteasome activity unde proteasome impairment. (2020)
  • Author(s): Shota Okuno, Eiichi Hashimoto, Shoshiro Hirayama, Hidetaka Kosako, Jun Hamazaki, and Shigeo Murata
  • Organizer: 第43回 日本分子生物学会年会
• [Presentation] RNF181 plays a pivotal role in O-GlcNAcylation-mediated cytoprotection under the proteasome impairment in canser cells (2019)
  • Author(s): Jun Hamazaki, Eiichi Hashimoto, Shota Okuno, Shohiro Hirayama, Hidetaka Kosako, Shigeo Murata
  • Organizer: 3rd EMBO Conferense Series, The ubiquitin system
  • Int'l Joint Research