Analysis of the mechanism of the degradation of aggregation prone proteiins by a novel ubiquitin binding protein CG5445

• Project/Area Number: 16K08228
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• 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): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: プロテアソーム / ユビキチン / タンパク質分解 / 分子生物学 / 神経変性疾患

Outline of Final Research Achievements

Ubiquitin-proteasome system (UPS) plays essential role in eukaryotes. Since ubiquitin including aggregates are observed in neurodegenerative diseases, disruption of UPS are considered to participate in pathogenic mechanism. We identified CG545 as a novel ubiquitin binding protein. We clarify CG5445 plays a role in degradation of ubiquitinated aggregation-prone proteins to decrease their cytotoxicity until they are degraded.

Academic Significance and Societal Importance of the Research Achievements

生体内における不要タンパク質除去に働く分解系のうち、ユビキチン-プロテアソーム系が凝集性タンパク質の分解にどのように働くかについては長い間様々な仮説が提唱されているものの、実態は不明であった。本課題において易凝集性タンパク質分解においてプロテアソーム機能を促進する分子としてCG5445を同定したことにより、プロテアソームが神経変性疾患をはじめとする病態発症に関与する分子機構の解明に大きな進歩をもたらすと考えられる。

Research Products

• [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
• [Journal Article] Structure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets. (2017)
  • Author(s): Lu X, Nowicka U, Sridharan V, Liu F, Ramdles L, Hymel D, Dyba M, Tarasov SG, Tarasova NI, Zhao XZ, Hamazaki J, Murata S, Burke TR Jr, Walters KJ.
  • Journal Title: nature communications Volume: 8 Issue: 1 Pages: 15540-15540
  • DOI: 10.1038/ncomms15540
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Early and consistent overexpression of ADRM1 in ovarian high-grade serous cartinoma. (2017)
  • Author(s): Jiang RT, Yemelyanova A, Xing D, Anchoori RK, Hamazaki J, Murata S, Seidman JD, Wang TL, Roden RBS.
  • Journal Title: Jounal of Ovarian Research Volume: 10 Issue: 1 Pages: 53-53
  • DOI: 10.1186/s13048-017-0347-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ubiquitin-Binding Protein CG5445 Suppresses Aggregation and Cytotoxicity of Amyotrophic Lateral Sclerosis-linked TDP-43 in Drosophila. (2017)
  • Author(s): Uechi H, Kuranaga E, Iriki T, Takano K, Hirayama S, Miura M, Hamazaki J, Murata S.
  • Journal Title: Molecular and Cellular Biology Volume: 3 Issue: 3
  • DOI: 10.1128/mcb.00195-17
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Foxn1-β5t transcriptional axis controls CD8+ T cell production in the thymus. (2017)
  • Author(s): Uddin MM, Ohigashi I, Motosugi R, Nakayama T, Sakata M, Hamazaki J, Nishito Y, Rode I, Tanaka K, Takemoto T, Murata S, Takahama Y.
  • Journal Title: Nat Commun Volume: 8 Issue: 1 Pages: 14419-14419
  • DOI: 10.1038/ncomms14419
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The aspartyl protease DDI2 activates Nrf1 to compensate for proteasome dysfunction. (2016)
  • Author(s): Koizumi S, Irie T, Hirayama S, Sakurai Y, Yashiroda H, Naguro I, Ichijo H, Hamazaki J, Murata S.
  • Journal Title: Elife Volume: 18357 Pages: 18357-18357
  • DOI: 10.7554/elife.18357
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] プロテアソーム不調と細胞恒常性維持 (2019)
  • Author(s): 濱崎純
  • Organizer: 第3回Fibrosis
  • Invited
• [Presentation] プロテアソーム不全時のO-GlcNAc修飾亢進による新規恒常性維持機構 (2019)
  • Author(s): 濱崎純
  • Organizer: 第1回新学術「ケモユビキチン」班会議・第2回ユビキチン研究会
• [Presentation] 精子形成過程におけるプロテアソーム相互作用因子PI31の機能解明 (2019)
  • Author(s): 福島聡真、入木朋洋、濱崎純、村田茂穂
  • Organizer: 第1回新学術「ケモユビキチン」班会議・第2回ユビキチン研究会
• [Presentation] プロテアソーム機能低下時に代償的に働く機構の網羅的探索 (2019)
  • Author(s): 橋本永一、濱崎純、村田茂穂
  • Organizer: 第1回新学術「ケモユビキチン」班会議・第2回ユビキチン研究会
• [Presentation] 哺乳類プロテアソームの細胞内局在はmTOR経路により制御される (2018)
  • Author(s): 松浦昌太郎、濱崎純、平山尚志郎、村田茂穂
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] ヒト全ゲノムスクリーニングによる哺乳類プロテアソーム機能制御因子の同定 (2018)
  • Author(s): 董瑶加、馬籠耕平、橋本永一、濱崎純、村田茂穂
  • Organizer: 第41回日本分子生物学会年会
• [Presentation] In vivo analysis of the proteasome inhibitor protein PI31 (2017)
  • Author(s): 入木朋洋、上地浩之、濱崎純、村田茂穂
  • Organizer: CIMR Grad Sch Pharm in Utokyo Workshop/Retreat program
  • Place of Presentation: 小田急山のホテル（神奈川県箱根町
  • Year and Date: 2017-01-31
• [Presentation] Genome-wide siRNA screening for factors maintaining cellular homeostasis under proteasome inhibition (2017)
  • Author(s): 橋本永一、濱崎純、村田茂穂
  • Organizer: 第3回4大学1研合同研究会
  • Place of Presentation: 秋保リゾートホテルクレセント(宮城県仙台市)
  • Year and Date: 2017-01-07
• [Presentation] Identification of the mechanism for Nrf1 activation in response to proteasome inhibition (2017)
  • Author(s): 小泉峻、濱崎純、村田茂穂
  • Organizer: 第3回4大学1研合同研究会
  • Place of Presentation: 秋保リゾートホテルクレセント(宮城県仙台市)
  • Year and Date: 2017-01-07
• [Presentation] プロテアソーム機能低下による細胞老化誘導機構の解明 (2017)
  • Author(s): 入木朋洋、橋本永一、平山尚志郎、濱崎純、村田茂穂
  • Organizer: 東京大学-同志社大学リトリート
• [Presentation] The Glycolytic pathway is required for cell survival under modest proteasome impairment (2017)
  • Author(s): 橋本永一、濱崎純、村田茂穂
  • Organizer: 第17回東京大学生命科学シンポジウム
• [Presentation] The Glycolytic pathway is required for cell survival under modest proteasome impairment (2017)
  • Author(s): 橋本永一、濱崎純、村田茂穂
  • Organizer: 東京大学-同志社大学リトリート
• [Presentation] Nrf1活性化に働く新規プロテアーゼDDI2阻害剤スクリーニング (2017)
  • Author(s): 高野滉平、小泉峻、平山尚志郎、濱崎純、村田茂穂
  • Organizer: 東京大学-同志社大学リトリート
• [Presentation] プロテアソーム発現制御転写因子Nrf1の活性化機構 (2017)
  • Author(s): 小泉峻、濱崎純、村田茂穂
  • Organizer: 東京大学-同志社大学リトリート
• [Presentation] The mechanism of cellular senescence induced by proteasome dysfunction (2017)
  • Author(s): Tomohiro Iriki, Eiichi Hasimoto, Shoshiro Hirayama, Jun Hamazaki, Shigeo Murata
  • Organizer: CIMR UTokyo Symposium 2017
  • Int'l Joint Research
• [Presentation] The mechanism of cellular senescence induced by proteasome dysfunction (2017)
  • Author(s): Tomohiro Iriki, Eiichi Hasimoto, Shoshiro Hirayama, Jun Hamazaki, Shigeo Murata
  • Organizer: Graduate Programme in Leaders in Life Innovation Joint Symposium with University of Tokyo
  • Int'l Joint Research
• [Presentation] The mechanism of cellular senescence induced by proteasome dysfunction (2017)
  • Author(s): Tomohiro Iriki, Eiichi Hasimoto, Shoshiro Hirayama, Jun Hamazaki, Shigeo Murata
  • Organizer: Stockholm-Tokyo University Partnership, Living longer and healthier in an ageing world
  • Int'l Joint Research
• [Presentation] The mechanism of cellular senescence induced by proteasome dysfunction (2017)
  • Author(s): Tomohiro Iriki, Eiichi Hasimoto, Shoshiro Hirayama, Jun Hamazaki, Shigeo Murata
  • Organizer: KCL-Institute of Psychiatry, Psychology & Neuroscience UT-GIPLLI Joint Symposium
  • Int'l Joint Research
• [Presentation] プロテアソーム発現制御転写因子Nrf1の活性化機構 (2017)
  • Author(s): 小泉峻、濱崎純、村田茂穂
  • Organizer: 2017年度生命科学系学会合同年次大会
  • Int'l Joint Research
• [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阻害剤探索 (2017)
  • Author(s): 高野滉平、小泉峻、濱崎純、村田茂穂
  • Organizer: 2017年度生命科学系学会合同年次大会
  • Int'l Joint Research
• [Presentation] 胸腺皮質特異的プロテアソームサブユニットβ5tの転写因子の同定 (2016)
  • Author(s): 本杉良、濱崎純、西籐泰昌、高浜洋介、村田茂穂
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜国際平和会議場（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] In vivo analysis of the proteasome inhibitor protein PI31 (2016)
  • Author(s): 入木朋洋、上地浩之、濱崎純、村田茂穂
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜国際平和会議場（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] プロテアソーム活性低下時に生じる転写因子Nrf1の活性化機構の解明 (2016)
  • Author(s): 小泉峻、濱崎純、村田茂穂
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜国際平和会議場（神奈川県横浜市）
  • Year and Date: 2016-11-30
• [Presentation] ヒト全ゲノムスクリーニングによるプロテアソーム機能制御因子の同定 (2016)
  • Author(s): 馬籠耕平、橋本永一、濱崎純、村田茂穂
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: 横浜国際平和会議場 (神奈川県横浜市)
  • Year and Date: 2016-11-30
• [Presentation] Identification of the mechanism for Nrf1 activation in response to proteasome inhibition (2016)
  • Author(s): Shun Koizumi, Jun Hamazaki, Shigeo Murata
  • Organizer: 3rd PROTEOSTASIS Action Meeting Proteostasis and its Biological Implications
  • Place of Presentation: Lisbon (Portugal)
  • Year and Date: 2016-11-02
  • Int'l Joint Research
• [Presentation] Uncovering the mechanism for maintaining cellular homeostasis under proteasome inhibition (2016)
  • Author(s): Eiichi Hashimoto、Jun Hamazaki、Shigeo Murata
  • Organizer: 3rd PROTEOSTASIS Action Meeting
  • Place of Presentation: Lisbon (Portugal)
  • Year and Date: 2016-11-02
  • Int'l Joint Research
• [Presentation] プロテアソームと酸化ストレスのクロストークの解析 (2016)
  • Author(s): 濱崎 純
  • Organizer: 第3回新学術領域研究「酸素生物学」全体班会議
  • Place of Presentation: 東京大学弥生講堂一条ホール（東京都文京区）
  • Year and Date: 2016-05-28
• [Presentation] Identification of the mechanism for Nrf1 activation in response to proteasome inhibition (2016)
  • Author(s): 小泉 峻、入江 太郎、濱崎 純、村田 茂穂
  • Organizer: 第16回東京大学生命科学シンポジウム
  • Place of Presentation: 東京大学駒場キャンパス 21 Komcee (東京都目黒区)