Studies on novel NF-kB activation mechanism through linear ubiquitination and its related disorders

• Project Area: Regulation of signal transduction by post-translational modifications and its pathogenic dysregulation
• Project/Area Number: 22117006
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Gunma University (2011-2014); Osaka University (2010)
• Principal Investigator: TOKUNAGA Fuminori 群馬大学, 生体調節研究所, 教授 (00212069)
• Co-Investigator(Kenkyū-buntansha): 植田 亮 大阪大学, 医学系研究科, 助教 (10445025)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥133,640,000 (Direct Cost: ¥102,800,000、Indirect Cost: ¥30,840,000); Fiscal Year 2014: ¥26,130,000 (Direct Cost: ¥20,100,000、Indirect Cost: ¥6,030,000); Fiscal Year 2013: ¥27,430,000 (Direct Cost: ¥21,100,000、Indirect Cost: ¥6,330,000); Fiscal Year 2012: ¥29,380,000 (Direct Cost: ¥22,600,000、Indirect Cost: ¥6,780,000); Fiscal Year 2011: ¥28,990,000 (Direct Cost: ¥22,300,000、Indirect Cost: ¥6,690,000); Fiscal Year 2010: ¥21,710,000 (Direct Cost: ¥16,700,000、Indirect Cost: ¥5,010,000)
• Keywords: 酵素 / タンパク質 / 細胞・ 組織 / シグナル伝達 / 免疫学 / 細胞・組織 / ユビキチン / 免疫 / 炎症 / 蛋白質 / 癌

Outline of Final Research Achievements

NF-κB is a critical signal transduction pathway to regulate immune and inflammatory responses, which are induced by various stimuli such as bacterial and viral infections and irradiation. We identified a novel physiological regulatory mechanism that is mediated by linearly linked ubiquitin molecules. We showed that genetic deficiency of a component of linear ubiquitin-generating enzyme (LUBAC) induces severe chronic dermatitis. Furthermore, we revealed that LUBAC activity is related with B cell lymphomas.

Research Products

• [Journal Article] Structures of CYLD USP with Met1- or Lys63-linked diubiquitin reveal mechanisms for dual specificity (2015)
  • Author(s): Sato, Y., Goto, E., Shibata, Y., Kubota, Y., Yamagata, A., Goto-Ito, S., Kubota, K., Inoue, J., Takekawa, M., Tokunaga, F. and Fukai, S.
  • Journal Title: Nat. Struct. Mol. Biol. Volume: 22 Issue: 3 Pages: 222-229
  • DOI: 10.1038/nsmb.2970
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A novel autosomal recessive mutation of DSG4 causes monilethrix through the ER stress response. (2015)
  • Author(s): Madoka Kato, Akira Shimizu, Yoko Yokoyama, Kyoichi Kaira, Yutaka Shimomura, Akemi Ishida-Yamamoto, Kiyoko Kamei, Fuminori Tokunaga, and Osamu Ishikawa
  • Journal Title: J. Invest. Dermatol. Volume: 135 Issue: 5 Pages: 1253-1260
  • DOI: 10.1038/jid.2015.12
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 8番目のユビキチン鎖、直鎖状ユビキチン鎖の機能と疾患への関わり： 炎症、免疫応答に重要なNF-κB経路の新しい制御機構 (2014)
  • Author(s): 徳永文稔
  • Journal Title: 化学と生物 Volume: 52 Pages: 716-718
• [Journal Article] Structural and functional analyses of DNA-sensing and immune activation by human cGAS (2013)
  • Author(s): Kazuki Kato, Ryohei Ishii, Eiji Goto, Ryuichiro Ishitani, Fuminori Tokunaga, and Osamu Nureki
  • Journal Title: PLoS One Volume: 8 Issue: 10 Pages: e76983-e76983
  • DOI: 10.1371/journal.pone.0076983
  • Peer Reviewed
• [Journal Article] Recruitment of the autophagic machinery to endosomes during infection is mediated by ubiquitin (2013)
  • Author(s): Naonobu Fujita et al.
  • Journal Title: J. Cell Biol. Volume: 203 Issue: 1 Pages: 115-128
  • DOI: 10.1083/jcb.201304188
  • Peer Reviewed / Open Access
• [Journal Article] Linear ubiquitination-mediated NF-κB regulation and its related disorders (2013)
  • Author(s): Fuminori Tokunaga
  • Journal Title: J. Biochem. Volume: 154 Issue: 4 Pages: 313-323
  • DOI: 10.1093/jb/mvt079
  • Peer Reviewed
• [Journal Article] 直鎖状ユビキチン化を介したNF-κB制御機構と疾患 (2013)
  • Author(s): 徳永文稔
  • Journal Title: 生化学 Volume: 85 Pages: 414-422
  • NAID: 10031184261
• [Journal Article] Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-κB regulation (2012)
  • 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
  • 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
  • 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
  • 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
• [Journal Article] LUBAC, a novel ubiquitin ligase for linear ubiquitination, is crucial for inflammation and immune responses (2012)
  • 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
  • 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 complex (2012)
  • 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
  • Peer Reviewed
• [Journal Article] Activation of nuclear factor-kappa B by linear ubiquitin chain assembly complex contributes to lung metastasis of osteosarcoma cells (2012)
  • Author(s): Tomonoga, M., et al.
  • Journal Title: Int.J.Oncol. Volume: 40 Pages: 409-417
  • DOI: 10.3892/ijo.2011.1209
  • Peer Reviewed
• [Journal Article] Sharpin is a component of the NF-κB activating linear ubiquitin chain assembly complex (2011)
  • 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
  • Peer Reviewed
• [Journal Article] SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis (2011)
  • Author(s): Ikeda, F., et al.
  • Journal Title: Nature Volume: 471 Issue: 7340 Pages: 637-641
  • DOI: 10.1038/nature09814
  • Peer Reviewed
• [Journal Article] Linear ubiquitin assembly complex negatively regulates RIG-I- and TRIM25-mediated type I interferon induction (2011)
  • Author(s): Kyung-Soo Inn, et al
  • Journal Title: Mol.Cell Volume: 41 Pages: 354-365
  • Peer Reviewed
• [Presentation] Linear ubiquitination-mediated NF-κB regulation. (2015)
  • Author(s): Fuminori Tokunaga
  • Organizer: 2nd International Symposium on Protein Modifications in Pathogenic Dysregulation of Signaling.
  • Place of Presentation: 東京大学医科学研究所（東京）
  • Year and Date: 2015-01-23
  • Invited
• [Presentation] Optineurinの直鎖状ユビキチン結合を介したNF-κB制御と疾患との関連 (2014)
  • Author(s): 及川大輔、石井亮平、中澤世識、石谷隆一郎、濡木理、徳永文稔
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2014-11-26
• [Presentation] CRISPR/Cas9法を用いたLUBAC欠損細胞の作製とNF-κB活性制御への影響 (2014)
  • Author(s): 後藤栄治、徳永文稔
  • Organizer: 第37回日本分子生物学会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2014-11-26
• [Presentation] OptineurinのNF-κBシグナル制御の細胞機構と疾患 (2014)
  • Author(s): 及川大輔、石井亮平、中澤世識、石谷隆一郎、濡木理、徳永文稔
  • Organizer: 第９回臨床外レス応答学会
  • Place of Presentation: 岡山大学（岡山市）
  • Year and Date: 2014-11-01
• [Presentation] 癌抑制遺伝子STK11による細胞死制御機構 (2014)
  • Author(s): 野口拓也、熊澤琢也、徳永文稔
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都国際会館（京都市）
  • Year and Date: 2014-10-17
• [Presentation] 直鎖状ユビキチン鎖生成を介したNF-κBシグナル制御の分子基盤 (2014)
  • Author(s): 徳永文稔
  • Organizer: 第87回日本生化学会大会
  • Place of Presentation: 京都国際会館（京都市）
  • Year and Date: 2014-10-16
  • Invited
• [Presentation] 新規LUBACシグナル複合体構成因子の探索と細胞機能解析 (2014)
  • Author(s): 及川大輔、中澤世識、徳永文稔
  • Organizer: 第66回日本細胞生物学会
  • Place of Presentation: 奈良県新公会堂（奈良市）
  • Year and Date: 2014-06-13
• [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
  • Year and Date: 2013-02-12
• [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
  • Year and Date: 2013-02-01
  • 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-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
  • Year and Date: 2012-12-14
  • 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
  • Year and Date: 2012-08-29
  • Invited
• [Presentation] Specific recognition of linear ubiquitin by A20 zinc finger 7 is involved in NF-κB regulation (2012)
  • Author(s): Tokunaga, F.
  • Organizer: Keystone Symposium
  • Place of Presentation: Whistler, Canada
  • Year and Date: 2012-03-21
• [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
  • Place of Presentation: 京都
  • Year and Date: 2011-09-23
• [Presentation] 直鎖状ポリユビキチン化によるNF-κB活性化制御と疾患 (2010)
  • Author(s): 徳永文稔
  • Organizer: BMB2010(ワークショップ)
  • Place of Presentation: 神戸ポートピアホテル(招待講演)
  • Year and Date: 2010-12-08
• [Presentation] 直鎖状ポリユビキチン修飾を介したNF-κB制御のB細胞リンパ腫発症における役割
  • Author(s): 徳永文稔
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
  • Invited
• [Presentation] 直鎖状ユビキチン鎖生成を介したNF-κBシグナル制御と疾患
  • Author(s): 徳永文稔
  • Organizer: 東京工業大学バイオサイエンスシンポジウム
  • Place of Presentation: 横浜
  • Invited
• [Presentation] ユビキチン修飾による細胞機能制御と疾患
  • Author(s): 徳永文稔
  • Organizer: 第60回北関東医学会総会
  • Place of Presentation: 前橋
  • Invited
• [Presentation] Linear ubiquitination-mediated NF-κB regulation mechanism and its related disorders
  • Author(s): Fuminori Tokunaga
  • Organizer: プロテイン・アイランド・松山(PIM)国際シンポジウム2013
  • Place of Presentation: 松山
  • Invited
• [Presentation] 直鎖状ポリユビキチン化を介したNF-κB制御と疾患
  • Author(s): 徳永文稔
  • Organizer: 第86回日本生化学会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] 直鎖状ユビキチン化を介するNF-κB制御に関わる脱ユビキチン化酵素と疾患
  • Author(s): 徳永文稔、西増弘志、石谷隆一郎、濡木理
  • Organizer: 病態プロテアーゼ学会
  • Place of Presentation: 大阪
• [Presentation] Down-regulation mechanism for LUBAC-induced NF-κB pathway
  • Author(s): Fuminori Tokunaga
  • Organizer: The 35th Naito Conference: The ubiquitin-proteasome system: From basic mechanisms to pathophysiological roles
  • Place of Presentation: Sapporo
• [Book] シグナル伝達研究最前線2012 (2012)
  • Author(s): 井上純一郎
  • Total Pages: 222
  • Publisher: 羊土社
• [Book] シグナル伝達研究最前線2012 (2012)
  • Author(s): 徳永文稔
  • Total Pages: 222
  • Publisher: 羊土社
• [Remarks] 群馬大学生体調節研究所分子細胞制御分野ホームページ
  • URL: http://www.imcr.gunma-u.ac.jp/lab/molcb/
• [Remarks] 群馬大学生体調節研究所ホームページ
  • URL: http://www.imcr.gunma-u.ac.jp/
• [Remarks] 新学術領域「修飾シグナル病」ホームページ
  • URL: http://shushoku-signal.com/
• [Remarks] 群馬大学生体調節研究所分子細胞制御分野ホームページ
  • URL: http://www.imcr.gunma-u.ac.jp/lab/molcb/
• [Remarks] 群馬大学生体調節研究所ホームページ
  • URL: http://www.imcr.gunma-u.ac.jp/
• [Remarks] 新学術領域「修飾シグナル病」ホームページ
  • URL: http://shushoku-signal.com/
• [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/
• [Remarks] 新学術領域研究 「修飾シグナル病」HP
  • URL: http://shushoku-signal.com/
• [Remarks]
  • URL: http://www.imcr.gunma-u.ac.jp/organization/1488.html
• [Remarks] 大阪大学大学院医学系研究科医化学教室
  • URL: http://www.cellbio.med.osaka-u.ac.jp/
• [Remarks] 新学術領域研究「修飾シグナル病」HP
  • URL: http://shushoku-signal.com/