Regulatory mechanism of intracellular dynamics of conformationally aberrant proteins and its pathophysiological significance

• Project/Area Number: 18H04022
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Murata Shigeo 東京大学, 大学院薬学系研究科(薬学部), 教授 (20344070)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥43,680,000 (Direct Cost: ¥33,600,000、Indirect Cost: ¥10,080,000); Fiscal Year 2021: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000); Fiscal Year 2020: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000); Fiscal Year 2019: ¥11,700,000 (Direct Cost: ¥9,000,000、Indirect Cost: ¥2,700,000); Fiscal Year 2018: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
• Keywords: 構造異常タンパク質 / ユビキチン / プロテアソーム / オートファジー / タウ / 神経変性疾患 / タンパク質品質管理 / 核外移行 / アグリソーム / ダイニン / プロテオスターシス / 凝集 / 神経変性 / 異常タンパク質 / 変性タンパク質 / siRNAスクリーニング

Outline of Final Research Achievements

It is essential for cell survival that structurally aberrant proteins generated by environmental stresses or genetic mutations be properly degraded by intracellular protein quality control mechanisms. Furthermore, it has been known that proteins that are not fully degraded within the cell are transported to specific locations within the cell and sequestered. We have identified several novel factors involved in transporting these abnormal proteins and clarified how each factor is involved in the subcellular localization of the abnormal proteins.

Academic Significance and Societal Importance of the Research Achievements

本研究により、異常タンパク質の輸送、隔離のための新たな経路と新たな分子メカニズムがあることがわかった。まだ基礎研究の段階であるが、構造異常タンパク質の発現、蓄積は、がん細胞、老化細胞、神経変性疾患における神経細胞において観察されることから、これら疾患の新規治療戦略の端緒となることが期待できる。

Research Products

• [Int'l Joint Research] National Cancer Institute(米国)
• [Journal Article] The effect of nutrient deprivation on proteasome activity in 4-week-old mice and 24-week-old mice (2022)
  • Author(s): Nobuyuki Tanahashi, Moeko Komiyama, Mina Tanaka, Yuta Yokobori Shigeo Murata, and Keiji Tanaka
  • Journal Title: Journal of Nutritional Biochemistry Volume: 0 Pages: 0-0
  • DOI: 10.1016/j.jnutbio.2022.108993
  • Peer Reviewed / Open Access
• [Journal Article] The ubiquitination-deubiquitination cycle on the ribosomal protein eS7A is crucial for efficient translation (2021)
  • Author(s): Takehara Yuka、Yashiroda Hideki、Matsuo Yoshitaka、Zhao Xian、Kamigaki Akane、Matsuzaki Tetsuo、Kosako Hidetaka、Inada Toshifumi、Murata Shigeo
  • Journal Title: iScience Volume: 24 Issue: 3 Pages: 102145-102145
  • DOI: 10.1016/j.isci.2021.102145
  • NAID: 120007182109
  • Peer Reviewed / Open Access
• [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] 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] 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] Stress- and ubiquitylation-dependent phase separation of the proteasome (2020)
  • Author(s): Yasuda Sayaka、Tsuchiya Hikaru、Kaiho Ai、Guo Qiang、Ikeuchi Ken、Endo Akinori、Arai Naoko、Ohtake Fumiaki、Murata Shigeo、Inada Toshifumi、Baumeister Wolfgang、Fernandez-Busnadiego Ruben、Tanaka Keiji、Saeki Yasushi
  • Journal Title: Nature Volume: 578 Issue: 7794 Pages: 296-300
  • DOI: 10.1038/s41586-020-1982-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Dynamic Regulation of Proteasome Expression (2019)
  • Author(s): Motosugi Ryo、Murata Shigeo
  • Journal Title: Frontiers in Molecular Biosciences Volume: 6
  • DOI: 10.3389/fmolb.2019.00030
  • 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
• [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] In-depth Analysis of the Lid Subunits Assembly Mechanism in Mammals (2019)
  • Author(s): Bai Minghui、Zhao Xian、Sahara Kazutaka、Ohte Yuki、Hirano Yuko、Kaneko Takeumi、Yashiroda Hideki、Murata Shigeo
  • Journal Title: Biomolecules Volume: 9 Issue: 6 Pages: 213-213
  • DOI: 10.3390/biom9060213
  • 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] Transcriptional regulation of the 26S proteasome by Nrf1 (2018)
  • Author(s): Koizumi S, Hamazaki J, Murata S.
  • Journal Title: Proceedings of the Japan Academy, Series B Volume: 94 Issue: 8 Pages: 325-336
  • DOI: 10.2183/pjab.94.021
  • NAID: 130007497652
  • ISSN: 0386-2208, 1349-2896
  • Year and Date: 2018-10-11
  • Peer Reviewed / Open Access
• [Journal Article] PAC1-PAC2 proteasome assembly chaperone retains the core α4-α7 assembly intermediates in the cytoplasm. (2018)
  • Author(s): Wu W, Sahara K, Hirayama S, Zhao X, Watanabe A, Hamazaki J, Yashiroda H, Murata S.
  • Journal Title: Gene to Cells Volume: 10 Issue: 10 Pages: 839-848
  • DOI: 10.1111/gtc.12631
  • Peer Reviewed / Open Access
• [Journal Article] Specific modification of aged proteasomes revealed by tag-exchangeable knock-in mice. (2018)
  • Author(s): Tomita, T., Hirayama, S., Sakurai, Y., Ohte, Y., Yoshihara, H., Saeki, Y., Hamazaki, J., and Murata, S.
  • Journal Title: Mol. Cell Biol. Volume: 39 Issue: 1
  • DOI: 10.1128/mcb.00426-18
  • Peer Reviewed / Open Access
• [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] Elucidation of the mechanism of cleavage of transcription factor Nrf1 by DDI2 (2021)
  • Author(s): Masakazu Shimooka, Jun Hamazaki, Shigeo Murata
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] 核のUFD経路の生理的意義の解明 (2021)
  • Author(s): 西澤晏理、平山尚志郎、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] MHCクラスIの細胞膜表面における発現と抗原提示に関与する新規因子の探索 (2021)
  • Author(s): 渡邊綾香、平山尚志郎、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] Screening of regulator of basal proteasome expression (2021)
  • Author(s): Madoka Yamamura, Ryo Motosugi, Jun Hamazaki, Shigeo Murata
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] 加齢依存的に凝集するタンパク質の同定とその生理的意義の解明 (2021)
  • Author(s): 小湊樹、平山尚志郎、村田茂穂
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] 26Sプロテアソームの細胞内局在制御機構とその生理学的意義の解明 (2021)
  • Author(s): 上羅彩加、平山尚志郎、村田茂穂
  • Organizer: 第44回日本分子生物学会年会
• [Presentation] 翻訳におけるリボソームタンパク質eS7のユビキチン化/脱ユビキチン化の重要性 (2021)
  • Author(s): 八代田英樹、竹原由香、松尾芳隆、Xian Zhao、 神垣あかね、松崎哲郎、小迫英尊、稲田利文、村田茂穂
  • Organizer: 酵母遺伝学フォーラム 第５４回研究報告会
• [Presentation] 哺乳類プロテアソームは細胞老化に伴い核内fociに局在し、p21分解やミトコンドリア活性の抑制に関わる (2021)
  • Author(s): 増田竣
  • Organizer: 第20回次世代を担う若手のためのファーマ・バイオフォーラム2021
• [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] Identification of factors modulating the clearance of aggregate-prone tau by genome-wide CRISPR screening (2020)
  • Author(s): Yusen Men, Shinpei Ao, Yasuyuki Sakurai, Shoshiro Hirayama, Shigeo Murata
  • 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] ダイニン依存的新規アグリソーム形成機構の解明 (2019)
  • Author(s): 安河内巧、伊藤隆裕、平山尚志郎、村田茂穂
  • Organizer: 第92回日本生化学会大会
• [Presentation] Identification of factors modulating the clearance of aggregated tau by genome-wide screening (2019)
  • Author(s): 青新平、櫻井靖之、平山尚志郎、村田茂穂
  • Organizer: 第92回日本生化学会大会
• [Presentation] 核および細胞質特異的なユビキチン依存性タンパク質分解機構の解明 (2019)
  • Author(s): 藤原歩夢、横森一泉、青新平、平山尚志郎、村田茂穂
  • Organizer: 第92回日本生化学会大会
• [Presentation] How cells respond to proteasome impairment (2019)
  • Author(s): Murata S
  • Organizer: Z-ZOMES Conference
  • Int'l Joint Research / Invited
• [Presentation] プロテアソームの機能制御と病態 (2019)
  • Author(s): 村田茂穂
  • Organizer: 第1回大阪骨関節コロキウム
  • Invited
• [Presentation] 易凝集性タンパク質のユビキチン依存的細胞内局在制御機構 (2019)
  • Author(s): 村田茂穂
  • Organizer: 第14回臨床ストレス応答学会
  • Invited
• [Presentation] プロテアソームの機能制御と病態 (2019)
  • Author(s): 村田茂穂
  • Organizer: Science Pioneers Consortium 2019
  • Invited
• [Presentation] A genome-wide siRNA screen reveals a new ubiquitin binding protein, which exports ubiquitinated proteins from the nucleus (2018)
  • Author(s): 平山尚志郎、伊藤隆裕、村田茂穂
  • Organizer: International Symposium on "Proteins; from the Cradle to the Grave"
  • Int'l Joint Research
• [Presentation] Cell cycle -dependent or -independent regulation of subcellular localization of mammalian proteasomes (2018)
  • Author(s): 平山尚志郎、松浦昌太郎、村田茂穂
  • Organizer: X-ZOMES Conference 2019
  • Int'l Joint Research
• [Presentation] How cells respond to proteasome impairment (2018)
  • Author(s): Shigeo Murata
  • Organizer: X-ZOMES Conference 2019
  • Int'l Joint Research / Invited
• [Presentation] How cells respond to proteasome impairment (2018)
  • Author(s): Shigeo Murata
  • Organizer: 8th workshop on proteasome and autophagy
  • Int'l Joint Research / Invited
• [Remarks] 研究室ホームページ
  • URL: https://tanpaku.f.u-tokyo.ac.jp
• [Remarks] 東京大学大学院薬学系研究科蛋白質代謝学教室
  • URL: http://www.f.u-tokyo.ac.jp/~tanpaku/
• [Remarks] 東京大学大学院薬学系研究科蛋白質代謝学教室ホームページ
  • URL: http://www.f.u-tokyo.ac.jp/~tanpaku/