ユビキチンネオバイオロジー：拡大するタンパク質制御システム

• Project Area: New aspect of the ubiquitin system : its enormous roles in protein regulation
• Project/Area Number: 24112001
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Research Institution: Kyoto University(2013-2016); Osaka University(2012)
• Principal Investigator: 岩井 一宏 京都大学, 医学研究科, 教授 (60252459)
• Co-Investigator(Kenkyū-buntansha): 駒田 雅之 東京工業大学, 大学院生命理工学研究科, 教授 (10225568) ; 嘉村 巧 名古屋大学, 理学研究科, 教授 (40333455) ; 佐伯 泰 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, 副参事研究員 (80462779)
• Project Period (FY): 2012-06-28 – 2017-03-31
• Project Status: Granted(Fiscal Year 2016)
• Budget Amount: ¥47,970,000 (Direct Cost : ¥36,900,000、Indirect Cost : ¥11,070,000); Fiscal Year 2016 : ¥9,360,000 (Direct Cost : ¥7,200,000、Indirect Cost : ¥2,160,000); Fiscal Year 2015 : ¥9,360,000 (Direct Cost : ¥7,200,000、Indirect Cost : ¥2,160,000); Fiscal Year 2014 : ¥13,130,000 (Direct Cost : ¥10,100,000、Indirect Cost : ¥3,030,000); Fiscal Year 2013 : ¥9,360,000 (Direct Cost : ¥7,200,000、Indirect Cost : ¥2,160,000); Fiscal Year 2012 : ¥6,760,000 (Direct Cost : ¥5,200,000、Indirect Cost : ¥1,560,000)
• Keywords: 生体分子 / ユビキチン / タンパク質 / 翻訳後修飾 / 領域内研究者交流 / 情報交換 / 研究技法共有

Outline of Annual Research Achievements

タンパク質性の翻訳後修飾因子であるユビキチンは、発見された経緯からタンパク質分解と関連して研究が発展した。しかし近年、ユビキチン修飾は分解以外の様式でもタンパク質の機能を制御して、広汎な生命現象に関与していることが明確となりつつある。ユビキチンは「ユビキチンコード」と定義できるほど多様な様式で標的タンパク質に付加されてそれらの機能を制御しており、生命科学におけるユビキチン修飾系の重要性は益々拡大すると想定されている。
今後の我が国のユビキチン研究の発展に不可欠である最先端の解析技術の開発と、ユビキチンコードによる新たな生命機能制御メカニズムの解析を進めるために、領域の計画研究の研究代表者と分担研究者が本研究課題に分担研究者あるいは連携研究者として加わり役割を分担して領域を運営している。
平成27年度には21の公募研究班が加わったので、7月に研究内容の紹介と領域内共同研究の発展を狙って公募研究班の研究内容を発表する第1回班会議を、領域の若手研究者の国際化を目指して若手が英語で発表する若手シンポジウムと同時開催した。当初は韓国人ユビキチン研究者を招へいした国際シンポジウムを同時開催する予定であったが、MARSのため開催が叶わなかったので、次年度に別の国際会議の開催を計画している。

Current Status of Research Progress

2 :  Research has progressed on the whole more than it was originally planned.

Reason

領域で配備した最新鋭の質量分析計によるユビキチン鎖の定量的、かつ高感度同定法、ユビキチン化基質同定法が広く共有されているので、計画研究の佐伯の研究室に配当する研究費を増額したが、配当増に相応しい共同研究が展開している。加えて、新規に領域に参画した公募研究班とも良好な研究交流が進んでおり、順調に推移していると評価される。

Strategy for Future Research Activity

平成28年度には12月にユビキチン系の発見でノーベル賞を受賞されたCiechanover博士をはじめ、韓国、アメリカから研究者を招へいして国際会議を開催する予定である。

Research Products

• [Journal Article] Immunoblot analysis of linear polyubiquitination of NEMO. (2015)
  • Author(s): Sasaki, Y., Fujita, H., Nakai, M., and Iwai, K.
  • Journal Title: Methods. Mol. Biol. Volume : 56 Pages : 297-309
  • DOI: doi: 10.1007/978-1-4939-2422-6_17.
• [Journal Article] Roles of linear ubiquitinylation, a crucial regulator of NF-κB and cell death, in the immune system. (2015)
  • Author(s): Sasaki, K. and Iwai, K.
  • Journal Title: Immunol. Rev. Volume : 266 Pages : 175-189
  • DOI: doi: 10.1111/imr.12308.
  • Peer Reviewed
• [Journal Article] The unexpected role of polyubiquitin chains in the formation of fibrillar aggregates. (2015)
  • Author(s): Morimoto, D., Walinda, E., Fukada, H., Sou, Y. S., Kageyama, S., Hoshino, M., Fujii, T., Tsuchiya, H., Saeki, Y., Arita, K., Ariyoshi, M., Tochio, H., Iwai, K., Namba, K., Komatsu, M., Tanaka, K., Shirakawa, M.
  • Journal Title: Nat. Commun Volume : 6 Pages : 6116
  • DOI: 10.1038/ncomms7116
  • Peer Reviewed
• [Journal Article] Gliotoxin suppresses NF-κB activation by selectively inhibiting linear ubiquitin chain assembly complex (LUBAC). (2015)
  • Author(s): Sakamoto, H., Egashira, S., Saito, N., Kirisako, T., Miller, S., Sasaki, Y., Matsumoto, T., Shimonishi, M., Komatsu, T., Terai, T., Ueno, T., Hanaoka, K., Kojima, H., Okabe, T., Wakatsuki, S., Iwai, K., (corresponding author) and Nagano, T
  • Journal Title: ACS Chem. Biol. Volume : 10 Pages : 675-681
  • DOI: 10.1021/cb500653y
  • Peer Reviewed
• [Journal Article] Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection. (2015)
  • Author(s): MacDuff, D. A., Reese, T. A,, Kimmey, J. M., Weiss, L. A., Song, C., Zhang, X., Kambal, A., Duan, E., Carrero, J. A., Boisson, B., Laplantine, E., Israel, A., Picard, C., Colonna, M., Edelson, B. T., Sibley, L. D., Stallings, C. L., Casanova, J. L., Iwai, K., Virgin, H. W.
  • Journal Title: eLife Volume : 4 Pages : e04494
  • DOI: 10.7554/eLife.04494
  • Peer Reviewed
• [Journal Article] IFN-γ or IFN-α ameliorates chronic proliferative dermatitis by inducing expression of linear ubiquitin chain assembly complex. (2014)
  • Author(s): Tamiya H, Terao M, Takiuchi T, Nakahara M, Sasaki Y, Katayama I, Yoshikawa H, and Iwai K.
  • Journal Title: J. Immunol. Volume : 192 Pages : 3793-3804
  • DOI: 10.4049/jimmunol.1302308
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. (2014)
  • Author(s): Rodgers, M. A., Bowman, J., Fujita, H., Orazio, N., Shi, M., Liang, Q., Amatya, R., Kelly, T. J., Iwai, K., Ting, J., and Jung, J. U.
  • Journal Title: J. Exp. Med. Volume : 211 Pages : 1333-1347
  • DOI: 10.1084/jem.20132486
  • Peer Reviewed
• [Journal Article] HOIL-1L Functions as the PKCζ Ubiquitin Ligase to Promote Lung Tumor Growth. (2014)
  • Author(s): Queisser, M. A., Dada, L. A., Deiss-Yehiely, N., Angulo, M., Zhou, G., Kouri, F. M., Knab, L. M., Liu, J., Stegh, A. H., DeCamp, M. M., Budinger, G. R., Chandel, N. S., Ciechanover, A., Iwai, K., and Sznajder, J. I.
  • Journal Title: Am. J. Respir. Crit. Care Med. Volume : 190 Pages : 688-698
  • DOI: 10.1164/rccm.201403-0463OC
  • Peer Reviewed
• [Journal Article] Linear ubiquitin chains: NF-κB signalling, cell death, and beyond. (2014)
  • Author(s): Iwai, K., Fujita, H., and Sasaki, Y.
  • Journal Title: Nature Rev. Mol. Cell Biol. Volume : 15 Pages : 503-508
  • DOI: 10.1038/nrm3836
  • Peer Reviewed
• [Journal Article] Ubiquitin chain elongation: An intriguing strategy. (2014)
  • Author(s): Iwai, K. and Tanaka, K.
  • Journal Title: Molecular Cell Volume : 56 Pages : 189–191
  • DOI: 10.1016/j.molcel.2014.10.009
• [Journal Article] Suppression of LUBAC-mediated linear ubiquitination by a specific interaction between LUBAC and the deubiquitinases CYLD and OTULIN. (2014)
  • Author(s): Takiuchi, T., Nakagawa, T., Tamiya, H., Fujita, H., Sasaki, Y., Saeki, Y., Takeda, H., Sawasaki, T., Buchberger, A., Kimura, T., and Iwai. K.
  • Journal Title: Genes Cells. Volume : 19 Pages : 254-272
  • DOI: 10.1111/gtc.12128
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Mechanism underlying IKK activation mediated by the linear ubiquitin chain assembly complex (LUBAC). (2014)
  • Author(s): Fujita, H., Rahighi, S., Akita, M., Kato, R., Sasaki, Y., Wakatsuki, S., and Iwai, K.
  • Journal Title: Mol. Cell. Biol. Volume : 34 Pages : 1322-1335
  • DOI: 10.1128/MCB.01538-13
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms. (2014)
  • Author(s): Yang, Y., Schmitz, R., et al.
  • Journal Title: Cancer Discov. Volume : 4 Pages : 480-493
  • DOI: 10.1158/2159-8290. CD-13-0915
  • Peer Reviewed
• [Journal Article] Defective immune responses in mice lacking LUBAC-mediated linear ubiquitination in B cells. (2013)
  • Author(s): Sasaki, Y., Sano, S., Nakahara, M., Murata, S., Kometani, K., Aiba, Y., Sakamoto, S., Watanabe, Y., Tanaka, K., Kurosaki, K. and Iwai, K.
  • Journal Title: EMBO J. Volume : 32 Pages : 2463-2476
  • DOI: 10.1038/emboj.2013.184
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Recruitment of the autophagic machinery to endosomes during infection is mediated by ubiquitin. (2013)
  • Author(s): Fujita, N., Morita, E., Itoh, T., Tanaka, A., Nakaoka, M., Osada, Y., Umemoto, T., Saitoh, T., Nakatogawa, H., Kobayashi, S., Haraguchi, T., Guan, J.L., Iwai, K., Tokunaga, F., Saito, K., Ishibashi, K., Akira, S., Fukuda, M., Noda, T., and Yoshimori, T.
  • Journal Title: J. Cell Biol. Volume : 203 Pages : 115-128
  • DOI: 10.1083/jcb.201304188
  • Peer Reviewed
• [Journal Article] Two coordinated mechanisms underlie TNFα-induced immediate and delayed IKK activation. (2013)
  • Author(s): Blackwell, K., Zhang, L., Workman, L.M., Ting, A.T., Iwai, K., Habelhah, H.
  • Journal Title: Mol. Cell. Biol. Volume : 33 Pages : 1901-1915
  • DOI: 10.1128/MCB.01416-12
  • Peer Reviewed
• [Journal Article] IOP1 protein is an external component of the human cytosolic iron-sulfur cluster assembly (CIA) machinery and functions in the MMS19 protein-dependent CIA pathway. (2013)
  • Author(s): Seki, M., Takeda, Y., Iwai, K., and Tanaka, K.
  • Journal Title: J. Biol. Chem. Volume : 288 Pages : 16680-16689
  • DOI: 10.1074/jbc.M112.416602.
  • Peer Reviewed
• [Presentation] Patho-physiological functions of a new type of ubiquitin modification, linear ubiquitination. (2015)
  • Author(s): Iwai, K.
  • Organizer: LLS Lecture, Northwestern University, Feinberg School of Medicine.
  • Place of Presentation: Chicago, IL, USA.
  • Year and Date: 2015-10-13
  • Invited
• [Presentation] Linear ubiquitin chains: a new regulator of NF-κB activation and cell death signaling. (2015)
  • Author(s): Iwai, K.
  • Organizer: 1st SPS International Symposium Xiamen University
  • Place of Presentation: Xiamen, China
  • Year and Date: 2015-06-13
  • Int'l Joint Research / Invited
• [Presentation] Phenotypical difference between mice lacking subunits of LUBAC ubiquitin ligase. (2014)
  • Author(s): Iwai, K.
  • Organizer: 1st International Symposium for New Aspects of the Ubiquitin Research
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2014-11-10
  • Invited
• [Presentation] Mechanism underlying linear ubiquitin-mediated NF-κB activation. (2014)
  • Author(s): Iwai, K.
  • Organizer: Benzon Symposium Nuclear regulation by ubiquitin
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2014-08-18 – 2014-08-21
• [Presentation] Linear ubiquitination : a new regulator of NF-κB and cell death signaling. (2014)
  • Author(s): Iwai, K.
  • Organizer: 2014 International Conference on Protein Metabolism & Diseases
  • Place of Presentation: Yangyang, Korea
  • Year and Date: 2014-07-09 – 2014-07-11
  • Invited
• [Presentation] Molecular mechanism and regulation of linear chain-mediated NF-κB activation. (2014)
  • Author(s): Fujita, H., Takiuchi, T., and Iwai, K.
  • Organizer: Cold Spring Harbor Asia Conference “ Protein Modifications & Homeostasis”
  • Place of Presentation: Suzhou, China
  • Year and Date: 2014-06-16 – 2014-06-20
  • Invited
• [Presentation] Linear Polyubiquitination: a Crucial Regulator of NF-κB Activation. (2014)
  • Author(s): Iwai, K.
  • Organizer: THE UEHARA MEMORIAL FOUNDATION SYMPOSIUM 2014, Innovative Medicine : Basic Research and Development.
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2014-06-14 – 2014-06-17
  • Invited
• [Presentation] Differential requirement of LUBAC-mediated linear polyubiquitination in CD40- or BCR-mediated canonical NF-κB activation in B cells (2013)
  • Author(s): Sasaki, Y., Fujita, H., and Iwai, K.
  • Organizer: The EMBO Conference “Ubiquitin and Ubiquitin-like Proteins: From structure to function”
  • Place of Presentation: Riva del Garda, Italy
  • Year and Date: 2013-10-01 – 2013-10-05
• [Presentation] Linear polyubiquitination: a new regulator of NF-κB activation. (2013)
  • Author(s): Iwai, K.
  • Organizer: The 35th Naito Conference “The Ubiquitin-Proteasome System: From Basic Mechanisms to Pathophysiological Roles”
  • Place of Presentation: Sapporo, Japan
  • Year and Date: 2013-07-09 – 2013-07-12
  • Invited
• [Presentation] Linear polyubiquitination: a new regulator of NF-κB activation. (2013)
  • Author(s): Iwai, K.
  • Organizer: The 38th FEBS congress symposium “Regulation of biological processes by ubiquitin and ubiquitin-like proteins in health and disease: proteolysis, autophagy and apoptosis”
  • Place of Presentation: St. Petersburg, Russia
  • Year and Date: 2013-07-06 – 2013-07-12
  • Invited
• [Remarks] 新学術領域【ユビキチンネオバイオロジー」拡大するタンパク質制御システム
  • URL: http://ubiquitin.jp/
• [Remarks] 新学術領域研究 ユビキチンネオバイオロジー：拡大するタンパク質制御システム
  • URL: http://ubiquitin.jp/