直鎖状ポリユビキチン鎖の選択的生成機構とその役割

• Project Area: New aspect of the ubiquitin system : its enormous roles in protein regulation
• Project/Area Number: 24112002
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Research Institution: Kyoto University
• Principal Investigator: 岩井 一宏 京都大学, 医学研究科, 教授 (60252459)
• Project Fiscal Year: 2012-06-28 – 2017-03-31
• Project Status: Granted(Fiscal Year 2016)
• Budget Amount: ¥203,060,000 (Direct Cost : ¥156,200,000、Indirect Cost : ¥46,860,000); Fiscal Year 2016 : ¥42,120,000 (Direct Cost : ¥32,400,000、Indirect Cost : ¥9,720,000); Fiscal Year 2015 : ¥42,120,000 (Direct Cost : ¥32,400,000、Indirect Cost : ¥9,720,000); Fiscal Year 2014 : ¥42,380,000 (Direct Cost : ¥32,600,000、Indirect Cost : ¥9,780,000); Fiscal Year 2013 : ¥42,120,000 (Direct Cost : ¥32,400,000、Indirect Cost : ¥9,720,000); Fiscal Year 2012 : ¥34,320,000 (Direct Cost : ¥26,400,000、Indirect Cost : ¥7,920,000)
• Keywords: 生体分子 / ユビキチン / NF-kappaB / 直鎖状ユビキチン鎖 / 直鎖状ポリユビキチン鎖

Outline of Annual Research Achievements

ユビキチン修飾系は分解のみならず多様な様式でタンパク質の機能を制御する翻訳後修飾系である。細胞内には多彩なユビキチン鎖が存在し、ユビキチン鎖の種類によってタンパク質の制御様式が異なる。研究代表者は新規にユビキチンN末端のメチオニンを介して形成される直鎖状ユビキチン鎖(M1鎖)を選択的に生成するLUBACユビキチンリガーゼを発見し、LUBACによるM1鎖形成が種々の刺激依存的なNF-κB活性化に関与することを報告してきた。
本研究では多様なユビキチン修飾：ユビキチンコードによる多彩な才能機能制御機構の解明の一環として、研究代表者が世界に先駆けて同定したM1鎖の生理的、病理学的役割、選択的M1鎖生成メカニズム、M1鎖生成阻害剤の免疫・アレルギー疾患治療薬としての可能性を検索している。
本年度はSHARPINを欠損したcpdmマウスとHOIL-1Lノックアウトマウスの交配実験を進め、SHARPINの欠損がより細胞を種々の刺激依存的な細胞死に高感受性にすることを明確にした。さらに、B細胞におけるLUBACの機能解析を進め、LUBACによる直鎖状ユビキチン鎖形成能が消失すると、B細胞はTLR4依存的に増殖するのではなく、細胞死が誘発されることを明確にした。

Current Status of Research Progress

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

Reason

当初の想定通り順調に研究を展開しており、中間評価でも「研究の進展は順調であり、優れた成果を上げている。今後の研究計画、経費の使用は妥当である。」との評価を頂いた。

Research Output

• [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
• [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
• [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
• [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: doi: 10.1111/gtc.12128.
• [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: doi: 10.1128/MCB.01538-13.
• [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, Mitala JJJr, Whiting A, Xiao W, Ceribelli M, Wright GW, Zhao H, Yang Y, Xu W, Rosenwald A, Ott G, Gascoyne RD, Connors JM, Rimsza LM, Campo E, Jaffe ES, Delabie J, Smeland EB, Braziel RM, Tubbs RR, Cook JR, Weisenburger DD, Chan WC, Wiestner A, Kruhlak MJ, Iwai K, Bernal F, Staudt LM
  • Journal Title: Cancer Discov. Volume : 4 Pages : 480-493
  • DOI: doi:10.1158/2159-8290. CD-13-0915
• [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
• [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
• [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
• [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
• [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] 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: doi:10.1038/emboj.2013.184
• [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: doi: 10.1083/jcb.201304188.
• [Presentation] Increased redox-active iron induces mitochondrial damage that recruits Parkin. (2014)
  • Author(s): Iwai, K. and Takeda, Y.
  • Organizer: The 17th Biennial Meeting of Society for Free Radical Research International. Symposium “Redox-Active Iron in Disease Pathology and Treatment”
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20140323-20140326
• [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
• [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
• [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
• [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
• [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: 20131001-20131005
• [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: 20130709-20130712
• [Presentation] Linear polyubiquitination: a new regulator of NF-κB activation. (2013)
  • Author(s): Iwai, K.
  • Organizer: he 38th FEBS congress
  • Place of Presentation: St. Petersburg, Russia
  • Year and Date: 20130706-20130712
• [Remarks] 京都大学・大学院医学研究科・細胞機能制御学
  • URL: http://www.mcp.med.kyoto-u.ac.jp/