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Construction of polyubiquitin chain specific molecular probes and their applications to histopathologic examinations.

Research Project

Project/Area Number 23657075
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Structural biochemistry
Research InstitutionGunma University

Principal Investigator

TOKUNAGA Fuminori  群馬大学, 生体調節研究所, 教授 (00212069)

Project Period (FY) 2011 – 2012
Project Status Completed (Fiscal Year 2012)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywordsユビキチン / 炎症 / NF-κB / 細胞内シグナル伝達 / 分子プローブ / シグナル伝達 / 細胞・組織 / 酵素 / タンパク質
Research Abstract

The ubiquitin system functions as a pivotal post-transcriptional modification in numerous cellular functions, including protein degradation and signal transduction. We identified that LUBAC (linear ubiquitin chain assembly complex) generates a novel type of Met1-linked linear polyubiquitin chain and specifically regulates the NF-κB pathway, which is a central signaling pathway for inflammatory and immune responses. In this study, we show that A20, a deubiquitinase, suppresses NF-κB activation by binding linear polyubiquitin via the C-terminal seventh zinc finger (ZF7), and we determined the crystal structures of A20 ZF7 in complex with linear diubiquitin. Importantly, we found that a tandem conjugate of three ZF7s is available as a high affinity molecular probe to detect linear poluubiquitin chain.

Report

(3 results)
  • 2012 Annual Research Report   Final Research Report ( PDF )
  • 2011 Research-status Report
  • Research Products

    (39 results)

All 2013 2012 2011 Other

All Journal Article (19 results) (of which Peer Reviewed: 19 results) Presentation (13 results) (of which Invited: 3 results) Book (4 results) Remarks (3 results)

  • [Journal Article] Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-κB regulation2012

    • Author(s)
      Fuminori Tokunaga, Hiroshi Nishimasu, Ryuichiro Ishitani, Eiji Goto, Takuya Noguchi, Kazuhiro Mio, Kiyoko Kamei, Averil Ma, Kazuhiro Iwai, and Osamu Nureki
    • Journal Title

      EMBO J

      Volume: 31 Pages: 3856-3870

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Analysis of NF-κB essential modulator (NEMO) binding to linear and lysine-linked ubiquitin chains and its role in the activation of NF-κB2012

    • Author(s)
      Tobias Kensche, Fuminori Tokunaga, Fumiyo Ikeda, Eiji Goto, Kazuhiro Iwai, and Ivan Dikic
    • Journal Title

      J. Biol. Chem.

      Volume: 287 Pages: 23626-23634

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Non-canonical UBA-UBL interaction mediates formation of linear ubiquitin chain assembly complex2012

    • Author(s)
      Hirokazu Yagi, Kazuhiro Ishimoto, Takeshi Hiromoto, Hiroaki Fujita, Tsunehiro Mizushima, Yoshinori Uekusa, Maho Yagi-Utsumi, Eiji Kurimoto, Masanori Noda, Susumu Uchiyama, Fuminori Tokunaga, Kazuhiro Iwai, and Koichi Kato
    • Journal Title

      EMBO Rep

      Volume: 13 Pages: 462-468

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Backbone and side chain 1H, 13C, and 15N assignments of ubiquitin-like domain of human HOIL-1L, an essential component of linear ubiquitin chain assembly complex2012

    • Author(s)
      Yoshinori Uekusa, Syunsuke Miura, Hiroaki Sasakawa, Eiji Kurimoto, Eri Sakata, Serve Oliver, Hirokazu Yagi, Fuminori Tokunaga,Kazuhiro Iwai, and Koichi Kato
    • Journal Title

      Biomol. NMR Assign.

      Volume: 6 Pages: 177-180

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Activation of nuclear factor-kappa B by linear ubiquitin chain assembly complex contributes to lung metastasis of osteosarcoma cells2012

    • Author(s)
      Masato Tomonaga, Nobuyuki Hashimoto, Fuminori Tokunaga, Megumi Onishi, Akira Myoui, Hideki Yoshikawa, and Kazuhiro Iwai
    • Journal Title

      Int. J.Oncol

      Volume: 40 Pages: 409-417

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] A novel NF-κB regulatory mechanism for inflammatory and immune responses by the LUBAC ubiquitin ligase complex2012

    • Author(s)
      Fuminori Tokunaga and Kazuhiro Iwai: Linear ubiquitination
    • Journal Title

      Endocrine J.

      Volume: 59 Pages: 641-652

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] LUBAC, a novel ubiquitin ligase for linear ubiquitination, is crucial for inflammation and immune responses2012

    • Author(s)
      Fuminori Tokunaga and Kazuhiro Iwai
    • Journal Title

      Microbes Infect.

      Volume: 14 Pages: 563-572

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-κB regulation2012

    • Author(s)
      Tokunaga F, Nishimasu H, Ishitani R, Goto E, Noguchi T, Mio K, Kamei K, Ma A, Iwai K, Nureki O
    • Journal Title

      EMBO J.

      Volume: 31 Issue: 19 Pages: 3856-3870

    • DOI

      10.1038/emboj.2012.241

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Analysis of nuclear factor-κB (NF-κB) essential modulator (NEMO) binding to linear and lysine-linked ubiquitin chains and its role in the activation of NF-κB.2012

    • Author(s)
      Kensche, T.
    • Journal Title

      J. Biol. Chem.

      Volume: 287 Issue: 28 Pages: 23626-23634

    • DOI

      10.1074/jbc.m112.347195

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A non-canonical UBA-UBL interaction forms the linear-ubiquitin-chain assembly complex.2012

    • Author(s)
      H.Yagi, K.Ishimoto, T.Hiromoto, H.Fujita, T.Mizushima, Y.Uekusa, M.Yagi-Utsumi, E.Kurimoto, M.Noda, S.Uchiyama, F.Tokunaga, K. Iwai, and K.Kato
    • Journal Title

      EMBO Rep.

      Volume: 13 Issue: 5 Pages: 462-468

    • DOI

      10.1038/embor.2012.24

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A novel NF-κB regulatory mechanism for inflammatory and immune responses by the LUBAC ubiquitin ligase complex.2012

    • Author(s)
      Tokunaga, F.
    • Journal Title

      Endocr. J.

      Volume: 59 Pages: 641-652

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] LUBAC, a novel ubiquitin ligase for linear ubiquitination, is crucial for inflammation and immune responses2012

    • Author(s)
      Tokunaga, F., et al.
    • Journal Title

      Microbes Infect.

      Volume: (in press) Issue: 7-8 Pages: 563-572

    • DOI

      10.1016/j.micinf.2012.01.011

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Backbone and side chain ^1H, ^<13>C, and ^<15>N assignments of the ubiquitin-like domain of human HOIL-1L, an essential component of linear ubiquitin chain assembly complex2012

    • Author(s)
      Y.Uekusa, S.Mimura, H.Sasakawa, E.Kurimoto, E.Sakata, S.Olivier, H.Yagi, F.Tokunaga, K.Iwai, K.Kato
    • Journal Title

      Biomol.NMR Assign.

      Volume: (in press) Issue: 2 Pages: 177-180

    • DOI

      10.1007/s12104-011-9350-1

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Activation of nuclear factor-kappa B by linear ubiquitin chain assembly complex contributes to lung metastasis of osteosarcoma cells2012

    • Author(s)
      Tomonoga, M., et al.
    • Journal Title

      Int.J.Oncol.

      Volume: 40 Pages: 409-417

    • DOI

      10.3892/ijo.2011.1209

    • Related Report
      2012 Annual Research Report 2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] SHARPIN is a component of the NF-κB activating linear ubiquitin assembly complex2011

    • Author(s)
      Fuminori Tokunaga, Tomoko Nakagawa, Masaki Nakahara, Yasushi Saeki, Masami Taniguchi, Shin-ichi Sakata, Keiji Tanaka, Hiroyasu Nakano, and Kazuhiro Iwai
    • Journal Title

      Nature

      Volume: 471 Pages: 633-636

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis2011

    • Author(s)
      Fumiyo Ikeda, Yonathan Lissanu Deribe, Sigrid S. Skanland, Benjamin Stieglitz, Caroline Grabbe, Sjoerd van WijK, Mirita Franz-Wachtel, Panchali Goswami, Vanja Nagy, Janos Terzic, Fuminori Tokunaga, Ariadne Androulidaki, Tomoko Nakagawa, Manolis Pasparakis, Kazuhiro Iwai, John P. Sundberg, Liliana Schaefer, Boris Macek, Katrin Rittinger, and Ivan Dikic
    • Journal Title

      Nature

      Volume: 471 Pages: 637-641

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Linear ubiquitin assembly complex negativelyregulates RIG-I- and TRIM25-mediated type I interferon induction2011

    • Author(s)
      Kyung-Soo Inn, Michaela U. Gack, Fuminori Tokunaga, Mude Shi, Lai-Yee Wong, Kazuhiro Iwai, and Jae U. Jung
    • Journal Title

      Mol. Cell

      Volume: 41 Pages: 354-365

    • Related Report
      2012 Final Research Report
    • Peer Reviewed
  • [Journal Article] Sharpin is a component of the NF-κB activating linear ubiquitin chain assembly complex2011

    • Author(s)
      Tokunaga, F., Nakagawa, T., Nakahara, M., Saeki, Y., Taniguchi, M., Sakata, S., Tanaka, K., Nakano, H., Iwai, I.
    • Journal Title

      Nature

      Volume: 471 Issue: 7340 Pages: 633-636

    • DOI

      10.1038/nature09815

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis2011

    • Author(s)
      Ikeda, F., et al.
    • Journal Title

      Nature

      Volume: 471 Issue: 7340 Pages: 637-641

    • DOI

      10.1038/nature09814

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Presentation] Linear ubiquitin binding via A20 zinc finger 7 is involved in the canonical NF-B regulation2013

    • Author(s)
      Fuminori Tokunaga, Hiroshi Nishimasu, Ryuichiro Ishitani, and Osamu Nureki
    • Organizer
      Frontiers in the immunology and inflammation: From molecules to disease.
    • Place of Presentation
      Tokyo
    • Year and Date
      2013-02-12
    • Related Report
      2012 Final Research Report
  • [Presentation] Activation and regulation mechanisms of the linear ubiquitination-mediated NF-κB pathway2013

    • Author(s)
      Fuminori Tokunaga
    • Organizer
      1st International Symposium on Protein Modification in Pathogenic Dysregulation of Signaling
    • Place of Presentation
      Tokyo
    • Year and Date
      2013-02-01
    • Related Report
      2012 Final Research Report
  • [Presentation] 直鎖状ユビキチン生成を介したNF-B制御とB細胞リンパ腫との連関2013

    • Author(s)
      徳永文稔
    • Organizer
      がん研究分野の特性を踏まえた支援活動公開シンポジウム
    • Place of Presentation
      東京
    • Year and Date
      2013-01-30
    • Related Report
      2012 Final Research Report
  • [Presentation] Linear ubiquitin binding via A20 zinc finger 7 is involved in the canonical NF-κB regulation.2013

    • Author(s)
      Tokunaga, F.
    • Organizer
      Frontiers in the immunology and inflammation: From molecules to disease.
    • Place of Presentation
      Tokyo、学術総合センター 一橋講堂
    • Related Report
      2012 Annual Research Report
  • [Presentation] Activation and regulation mechanisms of the linear ubiquitination-mediated NF-κB pathway.2013

    • Author(s)
      Tokunaga, F.
    • Organizer
      1st International Symposium on Protein Modification in Pathogenic Dysregulation of Signaling.
    • Place of Presentation
      Tokyo、東大医科研
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] A20の直鎖状ポリユビキチン鎖特異的結合を介したNF-B制御2012

    • Author(s)
      徳永文稔、西増弘志、石谷隆一郎、後藤栄治、野口拓也、岩井一宏、濡木理
    • Organizer
      第85回日本生化学会シンポジウム:ベールを脱いだユビキチン系の新機能
    • Place of Presentation
      福岡
    • Year and Date
      2012-12-16
    • Related Report
      2012 Final Research Report
  • [Presentation] 直鎖状ユビキチン形成とNF-Bシグナル伝達2012

    • Author(s)
      徳永文稔
    • Organizer
      応用数理学会数理医学研究部会オーガナイズドセッション
    • Place of Presentation
      稚内
    • Year and Date
      2012-08-30
    • Related Report
      2012 Final Research Report
  • [Presentation] Specific recognition of linear ubiquitin by A20 zinc finger 7 is involved in NF-κB regulation2012

    • Author(s)
      Fuminori Tokunaga
    • Organizer
      Keystone Symposium
    • Place of Presentation
      Whistler, Canada
    • Year and Date
      2012-03-21
    • Related Report
      2012 Final Research Report 2011 Research-status Report
  • [Presentation] 直鎖状ポリユビキチン鎖:NF-κB制御に関わる新たな修飾機構と疾患2012

    • Author(s)
      徳永文稔
    • Organizer
      第9回Osteoimmunology Forum
    • Place of Presentation
      東京
    • Year and Date
      2012-02-04
    • Related Report
      2012 Final Research Report
  • [Presentation] A20の直鎖状ポリユビキチン鎖特異的結合を介したNF-κB制御.2012

    • Author(s)
      徳永文稔
    • Organizer
      第85回日本生化学会大会
    • Place of Presentation
      福岡、福岡国際会議場
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] 直鎖状ユビキチン形成とNF-κBシグナル伝達.2012

    • Author(s)
      徳永文稔
    • Organizer
      応用数理学会
    • Place of Presentation
      稚内、全日空ホテル
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] LUBACによる直鎖状ポリユビキチン鎖形成を介したNF-κB制御と疾患2011

    • Author(s)
      徳永文稔、中原匡咲、岩井一宏
    • Organizer
      第84回日本生化学会シンポジウム:拡大するユビキチンバイオロジー
    • Place of Presentation
      京都
    • Year and Date
      2011-09-23
    • Related Report
      2012 Final Research Report
  • [Presentation] LUBACによる直鎖状ポリユビキチン鎖形成を介したNF-κB制御と疾患2011

    • Author(s)
      徳永文稔
    • Organizer
      第84回 日本生化学会大会シンポジウム(招待講演)
    • Place of Presentation
      京都
    • Related Report
      2011 Research-status Report
  • [Book] NF-B経路の多様なポリユビキチン鎖による制御と疾患2012

    • Author(s)
      徳永文稔
    • Publisher
      実験医学増刊号
    • Related Report
      2012 Final Research Report
  • [Book] シグナル伝達研究最前線20122012

    • Author(s)
      井上純一郎
    • Total Pages
      222
    • Publisher
      羊土社
    • Related Report
      2012 Annual Research Report
  • [Book] シグナル伝達研究最前線20122012

    • Author(s)
      徳永文稔
    • Total Pages
      222
    • Publisher
      羊土社
    • Related Report
      2011 Research-status Report
  • [Book] 新規直鎖状ポリユビキチン鎖生成によるNF-Bシグナル制御2011

    • Author(s)
      徳永文稔、岩井一宏
    • Publisher
      実験医学
    • Related Report
      2012 Final Research Report
  • [Remarks] 群馬大学生体調節研究所分子細胞制御分

    • URL

      http://www.imcr.gunma-u.ac.jp/lab/molcb/

    • Related Report
      2012 Final Research Report
  • [Remarks] 群馬大学 生体調節研究所 分子細胞制御分野HP

    • URL

      http://www.imcr.gunma-u.ac.jp/lab/molcb/

    • Related Report
      2012 Annual Research Report
  • [Remarks] 新学術領域研究 「修飾シグナル病」HP

    • URL

      http://shushoku-signal.com/

    • Related Report
      2012 Annual Research Report

URL: 

Published: 2011-08-05   Modified: 2019-07-29  

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