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Cell Biology of Proteasomes

Research Project

Project/Area Number 19H00997
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 44:Biology at cellular to organismal levels, and related fields
Research InstitutionTokyo Metropolitan Institute of Medical Science

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)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
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)
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
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。

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.

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。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Comments on the Screening Results   Annual Research Report
  • Research Products

    (43 results)

All 2022 2021 2020 2019

All Journal Article (23 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 23 results,  Open Access: 23 results) Presentation (18 results) (of which Int'l Joint Research: 3 results,  Invited: 18 results) Book (2 results)

  • [Journal Article] The effect of nutrient deprivation on proteasome activity in 4-week-old mice and 24-week-old mice2022

    • 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

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] TRIP12 promotes small-molecule-induced degradation through K29/K48-branched ubiquitin chains2021

    • Author(s)
      Kaiho-Soma Ai、Akizuki Yoshino、Igarashi Katsuhide、Endo Akinori、Shoda Takuji、Kawase Yasuko、Demizu Yosuke、Naito Mikihiko、Saeki Yasushi、Tanaka Keiji、Ohtake Fumiaki
    • Journal Title

      Molecular Cell

      Volume: 81 Issue: 7 Pages: 1411-1424.e7

    • DOI

      10.1016/j.molcel.2021.01.023

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [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.
    • Journal Title

      Autophagy

      Volume: 17 Pages: 2011-2036

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Loss of peptide: N -glycanase causes proteasome dysfunction mediated by a sugar-recognizing ubiquitin ligase2021

    • Author(s)
      Yoshida Yukiko、Asahina Makoto、Murakami Arisa、Kawawaki Junko、Yoshida Meari、Fujinawa Reiko、Iwai Kazuhiro、Tozawa Ryuichi、Matsuda Noriyuki、Tanaka Keiji、Suzuki Tadashi
    • Journal Title

      Proceedings of the National Academy of Sciences

      Volume: 118 Issue: 27

    • DOI

      10.1073/pnas.2102902118

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [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
    • Journal Title

      J Cell Sci

      Volume: 134 Issue: 22 Pages: 1-1

    • DOI

      10.1242/jcs.258653

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Stress- and ubiquitylation-dependent phase separation of the proteasome2020

    • 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

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Loss of Parkin contributes to mitochondrial turnover and dopaminergic neuronal loss in aged mice.2020

    • Author(s)
      Noda S, Sato S, Fukuda T, Tada N, Uchiyama Y, Tanaka K, Hattori N.
    • Journal Title

      Neurobiol Dis.

      Volume: 136 Pages: 104717-104717

    • DOI

      10.1016/j.nbd.2019.104717

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [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
    • Journal Title

      Nat. Commun.

      Volume: 11 Issue: 1 Pages: 1222-1222

    • DOI

      10.1038/s41467-020-15006-4

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Critical role of mitochondrial ubiquitination and the OPTN?ATG9A axis in mitophagy2020

    • Author(s)
      Yamano Koji、Kikuchi Reika、Kojima Waka、Hayashida Ryota、Koyano Fumika、Kawawaki Junko、Shoda Takuji、Demizu Yosuke、Naito Mikihiko、Tanaka Keiji、Matsuda Noriyuki
    • Journal Title

      Journal of Cell Biology

      Volume: 219 Issue: 9 Pages: 1-23

    • DOI

      10.1083/jcb.201912144

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ribosomal protein S7 ubiquitination during ER stress in yeast is associated with selective mRNA translation and stress outcome2020

    • Author(s)
      Matsuki Yasuko、Matsuo Yoshitaka、Nakano Yu、Iwasaki Shintaro、Yoko Hideyuki、Udagawa Tsuyoshi、Li Sihan、Saeki Yasushi、Yoshihisa Tohru、Tanaka Keiji、Ingolia Nicholas T.、Inada Toshifumi
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 19669-19669

    • DOI

      10.1038/s41598-020-76239-3

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A substrate-trapping strategy to find E3 ubiquitin ligase substrates identifies Parkin and TRIM28 targets2020

    • Author(s)
      Watanabe Masashi、Saeki Yasushi、Takahashi Hidehisa、Ohtake Fumiaki、Yoshida Yukiko、Kasuga Yusuke、Kondo Takeshi、Yaguchi Hiroaki、Suzuki Masanobu、Ishida Hiroki、Tanaka Keiji、Hatakeyama Shigetsugu
    • Journal Title

      Communications Biology

      Volume: 3 Issue: 1 Pages: 592-592

    • DOI

      10.1038/s42003-020-01328-y

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [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.
    • Journal Title

      Commun. Biol.

      Volume: 3 Issue: 1 Pages: 163-163

    • DOI

      10.1038/s42003-020-0882-8

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The HOIL-1L ligase modulates immune signalling and cell death via monoubiquitination of LUBAC2020

    • Author(s)
      Fuseya Yasuhiro、Fujita Hiroaki、Kim Minsoo、Ohtake Fumiaki、Nishide Akira、Sasaki Katsuhiro、Saeki Yasushi、Tanaka Keiji、Takahashi Ryosuke、Iwai Kazuhiro
    • Journal Title

      Nature Cell Biology

      Volume: 22 Issue: 6 Pages: 663-673

    • DOI

      10.1038/s41556-020-0517-9

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The PINK1-Parkin axis: An Overview.2020

    • Author(s)
      Tanaka K.
    • Journal Title

      Neurosci Res.

      Volume: S0168-0102 Pages: 30571-1

    • DOI

      10.1016/j.neures.2020.01.006

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Collided ribosomes form a unique structural interface to induce Hel2‐driven quality control pathways2019

    • Author(s)
      Ikeuchi Ken、Tesina Petr、Matsuo Yoshitaka、Sugiyama Takato、Cheng Jingdong、Saeki Yasushi、Tanaka Keiji、Becker Thomas、Beckmann Roland、Inada Toshifumi
    • Journal Title

      The EMBO Journal

      Volume: 38 Issue: 5

    • DOI

      10.15252/embj.2018100276

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Parkin recruitment to impaired mitochondria for nonselective ubiquitylation is facilitated by MITOL2019

    • Author(s)
      Koyano Fumika、Yamano Koji、Kosako Hidetaka、Tanaka Keiji、Matsuda Noriyuki
    • Journal Title

      Journal of Biological Chemistry

      Volume: 294 Issue: 26 Pages: 10300-10314

    • DOI

      10.1074/jbc.ra118.006302

    • NAID

      120006959752

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Parkin‐mediated ubiquitylation redistributes MITOL/March5 from mitochondria to peroxisomes2019

    • Author(s)
      Koyano Fumika、Yamano Koji、Kosako Hidetaka、Kimura Yoko、Kimura Mayumi、Fujiki Yukio、Tanaka Keiji、Matsuda Noriyuki
    • Journal Title

      EMBO reports

      Volume: 20 Issue: 12

    • DOI

      10.15252/embr.201947728

    • NAID

      120006942558

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [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

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Structural insights into ubiquitin recognition and Ufd1 interaction of Npl42019

    • Author(s)
      Sato Yusuke、Tsuchiya Hikaru、Yamagata Atsushi、Okatsu Kei、Tanaka Keiji、Saeki Yasushi、Fukai Shuya
    • Journal Title

      Nature Communications

      Volume: 10 Issue: 1 Pages: 5708-5708

    • DOI

      10.1038/s41467-019-13697-y

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Thymoproteasome and peptidic self2019

    • Author(s)
      Takahama Y, Ohigashi I, Murata S, Tanaka K.
    • Journal Title

      Immunogenetics

      Volume: 71 Issue: 3 Pages: 217-221

    • DOI

      10.1007/s00251-018-1081-3

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sugar-Recognizing Ubiquitin Ligases: Action Mechanisms and Physiology.2019

    • Author(s)
      Yoshida Y, Mizushima T, Tanaka K.
    • Journal Title

      Front Physiol.

      Volume: 10 Pages: 104-104

    • DOI

      10.3389/fphys.2019.00104

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Methods to measure ubiquitin chain length and linkage.2019

    • Author(s)
      Ohtake, F., Tsuchiya, H., Tanaka, K., and Saeki, Y.
    • Journal Title

      Methods Enzymol

      Volume: 618 Pages: 105-133

    • DOI

      10.1016/bs.mie.2018.12.019

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Detection of ubiquitination activity and identification of ubiquitinated substrates using TR-TUBE2019

    • Author(s)
      Yoshida, Y., Saeki, Y., Tsuchiya, H., and Tanaka, K.
    • Journal Title

      Methods Enzymol

      Volume: 618 Pages: 135-147

    • DOI

      10.1016/bs.mie.2018.12.032

    • ISBN
      9780128163597
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 私のプロテアソーム研究 ~温故知新~2022

    • Author(s)
      田中啓二
    • Organizer
      先端モデル動物支援プラットフォーム (AdAMS) 成果発表会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Proteo- and Organello-stasis Linked to Neurodegeneration2022

    • Author(s)
      Keiji TANAKA
    • Organizer
      JSN 63rd Annual Meeting Commemorative Lecture
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] オートファジーと栄養2022

    • Author(s)
      田中啓二
    • Organizer
      第39回日本微量栄養素学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 基礎研究余話「役に立たない研究」と「役に立つ研究」2022

    • Author(s)
      田中啓二
    • Organizer
      日本学術会議主催学術フォーラム 国際基礎科学年(IYBSSD2022) ~持続可能な世界のために
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Autophagy and Nutrition2022

    • Author(s)
      Keiji TANAKA
    • Organizer
      The 8th Asian Congress of Dietetics
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] プロテアソームの基礎から医学研究へ2022

    • Author(s)
      田中啓二
    • Organizer
      日本臨床ストレス応答学会 第16回大会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] プロテアソーム ~基礎から医学研究へ~2021

    • Author(s)
      田中啓二
    • Organizer
      第101回 北海道医学大会総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] プロテアソーム ~基礎から医学研究へ~2021

    • Author(s)
      田中啓二
    • Organizer
      星薬科大学 先端生命科学研究所 Webシンポジウム「新しい薬のモダリティ」
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] プロテアソーム ~基礎から最先端研究へ~2021

    • Author(s)
      田中啓二
    • Organizer
      第3回 ヒトレトロウイルス学共同研究セミナー
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] プロテアソーム ~ 基礎から医学応用へ ~2020

    • Author(s)
      田中啓二
    • Organizer
      第24回日本がん分子標的治療学会(基調講演 1)
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] プロテアソーム ~ 基礎から最先端研究へ ~2020

    • Author(s)
      田中啓二
    • Organizer
      第29回泌尿器科分子・細胞研究会:未知との遭遇~基礎研究は楽しい~ イブニングセミナー2
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] タンパク質分解:プロテアソームとオートファジー2020

    • Author(s)
      田中啓二
    • Organizer
      第24回日本肝臓学会大会:特別講演
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] プロテアソーム ~選択的なタンパク質リサイクルシステム~2020

    • Author(s)
      田中啓二
    • Organizer
      第13回オートファジー研究会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 細胞内恒常性機能維持機とがん・老化関連疾患.2019

    • Author(s)
      田中啓二
    • Organizer
      第4回 肺トランスレーショナルメデイシン研究会「肺線維症における細胞老化の意義と治療的応用」
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] The Proteasome ~ Action Mechanisms and Spatiotemporal Dynamics ~2019

    • Author(s)
      Keiji Tanaka
    • Organizer
      Ken-ichi Arai Memorial Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Phase Separated Proteasome Condensates: For Nuclear Proteolysis.2019

    • Author(s)
      Keiji Tanaka
    • Organizer
      Joint Annual Meeting of 71st JSCB & 19th PSSJ, Joint Symposium. Emerging concepts of protein science: From nanoscale to cells
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] プロテアソーム~ 相分離が拓く新しいタンパク質分解機構 ~2019

    • Author(s)
      田中啓二
    • Organizer
      第二回 形態解析ワークショップ - 多様な顕微鏡を用いて
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] The Proteasome : Stress and Phase Separation2019

    • Author(s)
      Keiji Tanaka
    • Organizer
      NIH-Japan-JSPS Symposium: Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [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
      2019 Annual Research Report
  • [Book] Medical Science Digest2019

    • Author(s)
      田中啓二
    • Total Pages
      35
    • Publisher
      ニューサイエンス社
    • Related Report
      2019 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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