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Elucidation of protein networks controlling proteasomal degradation

Research Project

Project/Area Number 18H03993
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 43:Biology at molecular to cellular levels, and related fields
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

SAEKI Yasushi  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, プロジェクトリーダー (80462779)

Co-Investigator(Kenkyū-buntansha) 新井 大祐  早稲田大学, 理工学術院, 講師(任期付) (20624951)
Project Period (FY) 2018-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥44,070,000 (Direct Cost: ¥33,900,000、Indirect Cost: ¥10,170,000)
Fiscal Year 2021: ¥10,270,000 (Direct Cost: ¥7,900,000、Indirect Cost: ¥2,370,000)
Fiscal Year 2020: ¥10,270,000 (Direct Cost: ¥7,900,000、Indirect Cost: ¥2,370,000)
Fiscal Year 2019: ¥10,270,000 (Direct Cost: ¥7,900,000、Indirect Cost: ¥2,370,000)
Fiscal Year 2018: ¥13,260,000 (Direct Cost: ¥10,200,000、Indirect Cost: ¥3,060,000)
Keywordsプロテアソーム / ユビキチン / タンパク質分解 / 質量分析 / 細胞分化
Outline of Final Research Achievements

In this study, we unraveled the molecular mechanisms driving proteasomal degradation in detail by investigating the molecular network centered on the proteasome and analyzing its changes to certain stressed conditions and cell differentiation. The major findings are as follows: 1) The ubiquitin-selective unfoldase p97-UFD1-NPL4 complex and the shuttle factor RAD23B are critically important for the selection of proteasomal substrates. 2) Under hyperosmotic stress, the proteasomes and ubiquitylated substrates undergo a liquid-liquid phase separation and form proteolytic droplets. 3) Expression level of ECPAS, a proteasome-binding molecule, increases during ES cell differentiation into neurons and is required for cell differentiation.

Academic Significance and Societal Importance of the Research Achievements

本研究では、高浸透圧ストレス下において、プロテアソームが分解のための細胞内液滴を形成すること、ユビキチン鎖とシャトル分子のマルチバレント相互作用が液-液相分離を駆動することを明らかにした(Nature 2020)。この研究成果はタンパク質分解の新たな様式であり、ライフサイエンス研究全般に大きなインパクトを与えた。また、ユビキチン依存的な液-液相分離の異常が、神経変性疾患で観察されるユビキチン陽性タンパク質封入体の形成に関与する可能性があり、神経変性疾患発症機構の理解につながる。また、プロテアソーム経路の分子機構の理解は、現在、爆発的に拡大しているユビキチン創薬の分子基盤となる研究である。

Report

(5 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (42 results)

All 2022 2021 2020 2019 2018 Other

All Int'l Joint Research (1 results) Journal Article (20 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 20 results,  Open Access: 17 results) Presentation (12 results) (of which Int'l Joint Research: 3 results,  Invited: 11 results) Book (3 results) Remarks (6 results)

  • [Int'l Joint Research] Max Planck Institute of Biochemistry(ドイツ)

    • Related Report
      2019 Annual Research Report
  • [Journal Article] ENTREP/FAM189A2 encodes a new ITCH ubiquitin ligase activator that is downregulated in breast cancer2022

    • Author(s)
      Takumi Tsunoda, Miho Riku, Norika Yamada, Hikaru Tsuchiya, Takuya Tomita, Minako Suzuki, Mari Kizuki, Akihito Inoko, Hideaki Ito, Kenta Murotani, Hideki Murakami, Yasushi Saeki, Kenji Kasai
    • Journal Title

      EMBO reports

      Volume: 23 Issue: 2

    • DOI

      10.15252/embr.202051182

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] RNA polymerase II condensate formation and association with Cajal and histone locus bodies in living human cells2021

    • Author(s)
      Imada Takashi、Shimi Takeshi、Kaiho Ai、Saeki Yasushi、Kimura Hiroshi
    • Journal Title

      Genes to Cells

      Volume: - Issue: 5 Pages: 298-312

    • DOI

      10.1111/gtc.12840

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Proteasome phase separation for degradation2020

    • Author(s)
      佐伯 泰、安田 さや香、土屋 光
    • Journal Title

      生化学

      Volume: 92 Issue: 6 Pages: 822-826

    • DOI

      10.14952/SEIKAGAKU.2020.920822

    • NAID

      40022454281

    • ISSN
      0037-1017
    • Year and Date
      2020-12-25
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel method to determine the chain length of the polyubiquitinated proteins2020

    • Author(s)
      土屋 光、佐伯 泰
    • Journal Title

      生化学

      Volume: 92 Issue: 1 Pages: 14-19

    • DOI

      10.14952/SEIKAGAKU.2020.920014

    • ISSN
      0037-1017
    • Year and Date
      2020-02-25
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Multi-Step Ubiquitin Decoding Mechanism for Proteasomal Degradation2020

    • Author(s)
      Tsuchiya Hikaru、Endo Akinori、Saeki Yasushi
    • Journal Title

      Pharmaceuticals

      Volume: 13 Issue: 6 Pages: 128-128

    • DOI

      10.3390/ph13060128

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] α-synuclein strains that cause distinct pathologies differentially inhibit proteasome2020

    • Author(s)
      Suzuki Genjiro、Imura Sei、Hosokawa Masato、Katsumata Ryu、Nonaka Takashi、Hisanaga Shin-Ichi、Saeki Yasushi、Hasegawa Masato
    • Journal Title

      eLife

      Volume: 9

    • DOI

      10.7554/elife.56825

    • Related Report
      2020 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
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] RQT complex dissociates ribosomes collided on endogenous RQC substrate SDD12020

    • Author(s)
      Matsuo Yoshitaka、Tesina Petr、Nakajima Shizuka、Mizuno Masato、Endo Akinori、Buschauer Robert、Cheng Jingdong、Shounai Okuto、Ikeuchi Ken、Saeki Yasushi、Becker Thomas、Beckmann Roland、Inada Toshifumi
    • Journal Title

      Nature Structural & Molecular Biology

      Volume: 27 Issue: 4 Pages: 323-332

    • DOI

      10.1038/s41594-020-0393-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] 最先端プロテオミクス解析を用いたユビキチン研究2020

    • Author(s)
      佐伯 泰
    • Journal Title

      Farumashia

      Volume: 56 Issue: 1 Pages: 21-25

    • DOI

      10.14894/faruawpsj.56.1_21

    • NAID

      130007779041

    • ISSN
      0014-8601, 2189-7026
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Stepwise multipolyubiquitination of p53 by the E6AP-E6 ubiquitin ligase complex2019

    • Author(s)
      Masuda Y, Saeki Y, Arai N, Kawai H, Kukimoto I, Tanaka K, Masutani C.
    • Journal Title

      J Biol Chem

      Volume: 294 Issue: 41 Pages: 14860-14875

    • DOI

      10.1074/jbc.ra119.008374

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [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] 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
      2018 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
      2018 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
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Deubiquitylases USP5 and USP13 are recruited to and regulate heat-induced stress granules through their deubiquitylating activities2018

    • Author(s)
      Xie Xuan、Matsumoto Shunsuke、Endo Akinori、Fukushima Toshiaki、Kawahara Hiroyuki、Saeki Yasushi、Komada Masayuki
    • Journal Title

      Journal of Cell Science

      Volume: 131 Issue: 8 Pages: 210856-210856

    • DOI

      10.1242/jcs.210856

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] HERC2 facilitates BLM and WRN helicase complex interaction with RPA to suppress G-quadruplex DNA.2018

    • Author(s)
      Wu W, Rokutanda N, Takeuchi J, Lai Y, Maruyama R, Togashi Y, Nishikawa H, Arai N, Miyoshi Y,Suzuki N, Saeki Y, Tanaka K, Ohta T.
    • Journal Title

      Cancer Res.

      Volume: 78 Issue: 22 Pages: 6371-6385

    • DOI

      10.1158/0008-5472.can-18-1877

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [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

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Sameuramide A, a new cyclic depsipeptide isolated from an ascidian of the family Didemnidae.2018

    • Author(s)
      Machida K, Arai D, Katsumata R, Otsuka S, Yamashita JK, Ye T, Tang S, Fusetani N, Nakao Y
    • Journal Title

      Bioorg. Med. Chem.

      Volume: 26 Issue: 13 Pages: 3852-3857

    • DOI

      10.1016/j.bmc.2018.06.042

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Kakeromamide A, a new cyclic pentapeptide inducing astrocyte differentiation isolated from the marine cyanobacterium2018

    • Author(s)
      Nakamura F, Maejima H, Kawamura M, Arai D, Okino T, Zhao M, Ye T, Lee J, Chang Y-T, Fusetan N, Nakao Y
    • Journal Title

      Bioorg.Med.Chem.Lett.

      Volume: - Issue: 12 Pages: 2206-2209

    • DOI

      10.1016/j.bmcl.2018.04.067

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] ユビキチン依存的なプロテアソームの液-液相分離2021

    • Author(s)
      佐伯 泰、土屋 光、遠藤彬則
    • Organizer
      第94回日本生化学大会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Understanding the ubiquitin-proteasome system by advanced proteomics2021

    • Author(s)
      Yasushi Saeki、Hikaru Tsuchiya、Takuya Tomita、Akinori Endo
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] RAD23BはLLPSを駆動するユビキチンデコーダーである2020

    • Author(s)
      遠藤彬則、土屋光、田中啓二、佐伯泰
    • Organizer
      第43回日本分子生物学会年会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] ケモテクノロジーと質量分析計を活用したユビキチンコードの解読2019

    • Author(s)
      佐伯 泰、遠藤彬則、土屋 光、大竹史明
    • Organizer
      日本ケミカルバイオロジー学会 第14回年会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] ユビキチン研究の新展開―相分離から分解誘導剤まで2019

    • Author(s)
      佐伯 泰
    • Organizer
      第19回 日本蛋白質科学会年会・第71回日本細胞生物学会大会 合同年次大会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Orbitrap Fusion Lumosを使った革新的ユビキチン研究2019

    • Author(s)
      佐伯 泰
    • Organizer
      サーモフィッシャーサイエンティフィック 質量分析フォーラム2019
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] ユビキチンによるタンパク質分解のしくみ:We will degrade you!2019

    • Author(s)
      佐伯 泰
    • Organizer
      第9回CSJ化学フェスタ
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] MSを用いたユビキチンシグナルの網羅的解析2019

    • Author(s)
      佐伯 泰
    • Organizer
      第11回 LC/MSワークショップ
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 高浸透圧ストレスによるプロテアソーム液滴形成と核内タンパク質分解2019

    • Author(s)
      佐伯 泰
    • Organizer
      第14回日本臨床ストレス応答学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Stress- and ubiquitylation-dependent phase separation of the proteasome2019

    • Author(s)
      Yasushi Saeki
    • Organizer
      42nd MBSJ, Symposium ”Frontiers of in-cell protein sciences”
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Ub-ProT reveals global length and composition of protein ubiquitylation in cells.2018

    • Author(s)
      Yasushi Saeki
    • Organizer
      The 8th Proteasome and Autophagy Congress.
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The Cdc48-Rad23/Dsk2 Axis Contributes to K48 Ubiquitin Chain Specificity of the Proteasome.2018

    • Author(s)
      Yasushi Saeki
    • Organizer
      FASEB SRC “Ubiquitin and Cellular Regulation”
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Book] 相分離 メカニズムと疾患2021

    • Author(s)
      佐伯 泰
    • Total Pages
      8
    • Publisher
      羊土社
    • ISBN
      9784758103954
    • Related Report
      2021 Annual Research Report
  • [Book] 相分離生物学の全貌2020

    • Author(s)
      土屋 光、佐伯 泰
    • Total Pages
      5
    • Publisher
      東京化学同人
    • Related Report
      2020 Annual Research Report
  • [Book] イメージング時代の構造生命科学2020

    • Author(s)
      安田さや香、田中啓二、佐伯 泰
    • Total Pages
      6
    • Publisher
      羊土社
    • ISBN
      9784758103855
    • Related Report
      2019 Annual Research Report
  • [Remarks] 公益財団東京都医学総合研究所蛋白質代謝プロジェクトホームページ

    • URL

      https://www.igakuken.or.jp/pro-meta/

    • Related Report
      2021 Annual Research Report
  • [Remarks] 東京大学大学院新領域創成科学研究科メディカル情報生命専攻ホームページ

    • URL

      http://www.cbms.k.u-tokyo.ac.jp/lab/rinsho.html#saeki

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
  • [Remarks] 公益財団東京都医学総合研究所研究室ホームページ

    • URL

      https://www.igakuken.or.jp/pro-meta/

    • Related Report
      2020 Annual Research Report
  • [Remarks] 公益財団法人東京都医学総合研究所蛋白質代謝研究室ホームページ

    • URL

      http://www.igakuken.or.jp/pro-meta/

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
  • [Remarks] 液-液相分離が担う核内タンパク質分解機構の発見

    • URL

      http://www.igakuken.or.jp/topics/2020/0205.html

    • Related Report
      2019 Annual Research Report
  • [Remarks] Proteasome Phase separation for destruction

    • URL

      http://www.igakuken.or.jp/english/topics/2020/e-0206.html

    • Related Report
      2019 Annual Research Report

URL: 

Published: 2018-04-23   Modified: 2023-01-30  

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