New aspect of the ubiquitin system : its enormous roles in protein regulation

• 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
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: IWAI Kazuhiro 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, 生命理工学研究科, 教授 (10225568) ; 嘉村 巧 名古屋大学, 理学(系)研究科(研究院), 教授 (40333455) ; 佐伯 泰 公益財団法人東京都医学総合研究所, その他部局等, その他 (80462779)
• Project Period (FY): 2012-06-28 – 2017-03-31
• Project Status: Completed (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: 領域内研究者交流 / 情報交換 / 若手支援 / 国際化推進 / 研究技法共有 / 生体分子 / ユビキチン / タンパク質 / 翻訳後修飾

Outline of Final Research Achievements

Ubiquitin, a proteinous post-translational modifier, has been studied as a part of protein degradation system. However, it is now widely recognized that the ubiquitin system is involved in the regulation of a wide variety of biological phenomena by modulating protein functions in many ways. Since dissection methods of the ubiquitin system become diversified and highly developed, it is almost impossible to do all the dissections in one laboratory. “New aspect of the ubiquitin system : its enormous roles in protein regulation”, an research area of Grant-in-Aid for Scientific Research on Innovative Areas was organized to develop cutting-edge technologies to dissect the ubiquitin system and tried to identify new roles of the ubiquitin system in the regulation of biological phenomena. This research project is a headquarter of the research area and handled advertisement, organizing conference for young as well as foreign researchers and promoting collaborations within research areas.

Research Products

• [Journal Article] Roles of the NF-kappaB Pathway in B-Lymphocyte Biology. (2016)
  • Author(s): Sasaki, Y. and Iwai, K.
  • Journal Title: Curr. Top. Microbiol. Immunol. Volume: 393 Pages: 177-209
  • DOI: 10.1007/82_2015_479
• [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: 1280 Pages: 297-309
  • DOI: 10.1007/978-1-4939-2422-6_17
  • Acknowledgement Compliant
• [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: 10.1111/imr.12308
  • NAID: 120005672572
  • 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., and Shirakawa M.
  • Journal Title: Nat Commun. Volume: 6 Pages: 000-000
  • DOI: 10.1038/ncomms7116
  • NAID: 120005528125
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Gliotoxin Suppresses NF-κB Activation by Selectively Inhibiting Linear Ubiquitin Chain Assembly Complex (LUBAC) (2015)
  • Author(s): Hiroki Sakamoto, Shinichiro Egashira, Nae Saito, Takayoshi Kirisako, Simon Miller, Yoshiteru Sasaki, Tadahiko Matsumoto, Manabu Shimonishi, Toru Komatsu, Takuya Terai, Tasuku Ueno, Kenjiro Hanaoka, Hirotatsu Kojima, Takayoshi Okabe, Soichi Wakatsuki, Kazuhiro Iwai, Tetsuo Nagano
  • Journal Title: ACS Chem. Biol. Volume: 10 Pages: 675-681
  • DOI: 10.1021/cb500653y
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
  • DOI: 10.7554/elife.04494
  • NAID: 120005997705
  • Peer Reviewed
• [Journal Article] IFN-γ or IFN-α Ameliorates Chronic Proliferative Dermatitis (cpdm) by Inducing Expression of Linear Ubiquitin Chain Assembly Complex (LUBAC). (2014)
  • Author(s): Tamiya H, Terao M, Takiuchi T, Nakahara M, Sasaki Y, Katayama I, Yoshikawa H, and Iwai K.
  • Journal Title: Journal of Immunology. Volume: 192 Pages: 3793-3804
  • DOI: 10.4049/jimmunol.1302308
  • Peer Reviewed / Open Access / 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 signaling, cell death and beyond. (2014)
  • Author(s): Iwai, K., Fujita, H., and Sasaki, Y.
  • Journal Title: Nat. 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
  • 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 / Open Access / Acknowledgement Compliant
• [Journal Article] Mechanism underlying IKK activation mediated by the linear ubiquitin 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 / Open Access / 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, T., and lwai, 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 upstream of LC3 is mediated by ubiquitin on host endosomal membranes during infection-induced autophagy. (2013)
  • Author(s): Naonobu Fujita et al.
  • Journal Title: J Cell Biol Volume: 203 Pages: 115-128
  • DOI: 10.1083/jcb.201304188
  • Peer Reviewed / Open Access
• [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 is an external component of human CIA machinery and functions in MMS19-dependent CIA pathway (2013)
  • Author(s): Mineaki Seki, Yukiko Takeda, Kazuhiro Iwai and Kiyoji Tanaka
  • Journal Title: J. Biol. Chem. Volume: 288 Pages: 16680-16689
  • DOI: 10.1074/jbc.m112.416602
  • Peer Reviewed / Acknowledgement Compliant
• [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 Pages: 3856-3856
  • DOI: 10.1038/emboj.2012.241
  • Peer Reviewed
• [Journal Article] Linear Ubiquitination of NEMO Negatively Regulates the Interferon Antiviral Response through Disruption of the MAVS-TRAF3 Complex (2012)
  • Author(s): Belgnaoui, SM.
  • Journal Title: Cell Host Microbe. Volume: 12 Pages: 211-222
  • DOI: 10.1016/j.chom.2012.06.009
  • 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 Pages: 23626-23634
  • DOI: 10.1074/jbc.m112.347195
  • Peer Reviewed
• [Journal Article] Diverse ubiquitin signaling in NF-κB activation. (2012)
  • Author(s): Iwai, K.
  • Journal Title: Trends Cell Biol. Volume: 22 Pages: 355-364
  • DOI: 10.1016/j.tcb.2012.04.001
  • Peer Reviewed
• [Presentation] Pathophysiology of the atypical linear ubiquitin chain (2016)
  • Author(s): Iwai, K
  • Organizer: Diverse functions of Ubiquitin : Degradation, Signaling, and Beyond
  • Place of Presentation: Kyoto Japan
  • Int'l Joint Research / Invited
• [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
• [Presentation] Linear polyubiquitination : A crucial regulator of NF-kB signaling (2012)
  • Author(s): Iwai, K.
  • Organizer: The 3rd International Symposium "Signaling and Regulation in the Immune and Nervous Systems
  • Place of Presentation: Magdeburg, Germany
  • Year and Date: 2012-11-22
  • Invited
• [Presentation] Linear polyubiquitination: A crucial regulator of NF-κB signalling (2012)
  • Author(s): Fujita, H.
  • Organizer: ZOMESVII conference
  • Place of Presentation: Munich Germany
  • Year and Date: 2012-09-18
  • Invited
• [Presentation] Mechanism underlying generation of linear polyubiquitin chains (2012)
  • Author(s): Iwai, K
  • Organizer: 4th Annual Ubiquitin Drug Discovery Diagnostics Conference 2012
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2012-07-23
  • 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【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/
• [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/
• [Funded Workshop] Diverse functions of Ubiquitin : Degradation, Signaling, and Beyond (2016)
  • Place of Presentation: 京都大学