Elucidating the role of branched ubiquitin code

• Project/Area Number: 17H03986
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Hoshi University (2019-2020); Tokyo Metropolitan Institute of Medical Science (2017-2018)
• Principal Investigator: Ohtake Fumiaki 星薬科大学, 先端生命科学研究所, 特任准教授 (60447373)
• Co-Investigator(Kenkyū-buntansha): 土屋 光 公益財団法人東京都医学総合研究所, 生体分子先端研究分野, 主任研究員 (90760132)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2020: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2017: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
• Keywords: ユビキチン / 標的タンパク質分解 / プロテアソーム / アポトーシス / PROTAC / タンパク質分解誘導剤 / 翻訳後修飾 / タンパク質分解 / タンパク質 / シグナル伝達 / 蛋白質

Outline of Final Research Achievements

Post-translational modification of proteins with ubiquitin regulates numerous biological pathways such as proteasomal protein degradation, inflammation, and DNA repair. However, how different ubiquitin signals are integrated to govern complex biological outputs remains largely unknown. In this study, we identified UBR5 and TRIP12 as ubiquitin chain branching factors. UBR5 modifies TXNIP with K48/K63 branched ubiquitin chains to promote its proteasomal degradation.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、分岐型ユビキチン鎖がタンパク質分解を促進することが明らかとなり、その責任酵素の一端を解明した。ユビキチン修飾系の異常は様々な疾患の原因となっており、ユビキチン化の詳細なメカニズムの解明は、将来的に、疾患発症機構の解明につながる可能性が期待される。

Research Products

• [Journal Article] TRIP12 promotes small-molecule-induced degradation through K29/K48-branched ubiquitin chains (2021)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] MIND bomb 2 prevents RIPK1 kinase activity-dependent and -independent apoptosis through ubiquitylation of cFLIPL (2021)
  • Author(s): Nakabayashi Osamu、Takahashi Hirotaka、Moriwaki Kenta、Komazawa-Sakon Sachiko、Ohtake Fumiaki、Murai Shin、Tsuchiya Yuichi、Koyahara Yuki、Saeki Yasushi、Yoshida Yukiko、Yamazaki Soh、Tokunaga Fuminori、Sawasaki Tatsuya、Nakano Hiroyasu
  • Journal Title: Communications Biology Volume: 4 Issue: 1 Pages: 80-80
  • DOI: 10.1038/s42003-020-01603-y
  • Peer Reviewed / Open Access
• [Journal Article] A substrate-trapping strategy to find E3 ubiquitin ligase substrates identifies Parkin and TRIM28 targets (2020)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] The HOIL-1L ligase modulates immune signalling and cell death via monoubiquitination of LUBAC (2020)
  • 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
  • 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] 分岐型ユビキチン鎖とアセチル化ユビキチン (2020)
  • Author(s): 大竹史明
  • Journal Title: 生化学 Volume: 91 Pages: 57-63
• [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
  • Peer Reviewed / Open Access
• [Journal Article] K63 ubiquitylation triggers proteasomal degradation by seeding branched ubiquitin chains. (2018)
  • Author(s): Ohtake, F., Tsuchiya, H., Saeki, Y., and Tanaka, K
  • Journal Title: PNAS Volume: 115 Issue: 7 Pages: 1401-1408
  • DOI: 10.1073/pnas.1716673115
  • Peer Reviewed
• [Journal Article] Ub-ProT reveals global length and composition of protein ubiquitylation in cells (2018)
  • Author(s): Tsuchiya, H., Burana, D., Ohtake, F., Arai, N., Kaiho, A., Komada, M., Tanaka,K., and Saeki, Y.
  • Journal Title: Nature Commun Volume: 9 Issue: 1 Pages: 524-524
  • DOI: 10.1038/s41467-018-02869-x
  • Peer Reviewed / Open Access
• [Presentation] Role of ubiquitin chain architecture revealed by chemo-technology (2020)
  • Author(s): Fumiaki Ohtake
  • Organizer: 第93回日本生化学会
  • Invited
• [Presentation] プロテオミクス解析から明らかになるユビキチン修飾のバイオロジー (2020)
  • Author(s): 大竹史明
  • Organizer: 第68回質量分析総合討論会
  • Invited
• [Presentation] 質量分析技術とケミカルツールでユビキチン鎖の複雑性に挑む (2019)
  • Author(s): 大竹史明
  • Organizer: 第4回先端ケミカルバイオロジー研究会
  • Invited
• [Presentation] Proteomic analysis of K48/K63 branched ubiquitin chains. (2019)
  • Author(s): Ohtake F, Naito M, Saeki Y, Tanaka K.
  • Organizer: EMBO Conference「The ubiquitin system: Biology, mechanism, and roles in disease」
• [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
  • Invited
• [Presentation] 分岐型ユビキチン鎖によるタンパク質分解制御機構 (2019)
  • Author(s): 大竹史明
  • Organizer: 第8回TOBIRA研究フォーラム
• [Presentation] The ubiquitin ligases ITCH and UBR5 regulate proteasomal degradation through K48/K63 branched ubiquitin chains (2018)
  • Author(s): Ohtake F, Saeki Y, Tanaka K.
  • Organizer: 第41回日本分子生物学会シンポジウム
  • Invited
• [Presentation] Post-translational modification code of ubiquitin in signal transduction and protein degradation (2018)
  • Author(s): Ohtake F, Saeki Y, Tanaka K.
  • Organizer: 第91回日本生化学会シンポジウム
  • Invited
• [Presentation] The NEDD4 family ubiquitin ligase ITCH regulates proteasomal degradation by seeding branched ubiquitin chains. (2018)
  • Author(s): Ohtake F, Saeki Y, Tanaka K.
  • Organizer: FASEB Conference「Ubiquitin and cellular regulation」
  • Int'l Joint Research
• [Presentation] 炎症応答を制御する新たなユビキチン・シグナル (2017)
  • Author(s): 大竹史明、田中啓二
  • Organizer: 第44回日本毒性学会
  • Invited
• [Presentation] Role of the K48/K63 branched ubiquitin chains in signal transduction and proteasomal degradation. (2017)
  • Author(s): Ohtake F., Tanaka K.
  • Organizer: EMBO conference「Ubiquitin and SUMO」
  • Int'l Joint Research
• [Presentation] 出芽酵母におけるK48/K63分岐型ポリユビキチン鎖の解析 (2017)
  • Author(s): 河野有紗、大竹史明、佐伯泰、田中啓二
  • Organizer: 2017年度生命科学系学会合同年次大会
• [Remarks] 蛋白質代謝研究室ホームページ
  • URL: http://www.igakuken.or.jp/pro-meta/