Generation and function of linear ubiquitin chains

• 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)
• 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)
• Project Period (FY): 2012-06-28 – 2017-03-31
• Project Status: Completed (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: 直鎖状ユビキチン鎖 / ユビキチン / NF-kappaB / Bリンパ球 / B細胞リンパ腫 / アスペルギルス / 生体分子 / 直鎖状ポリユビキチン鎖 / 直鎖状ポリユビキチン鎖阻害剤 / B細胞

Outline of Final Research Achievements

The ubiquitin conjugation system is one of the most important reversible post-translational modification system that regulates functions of proteins in a wide variety of ways. This is one of the eight research projects of 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. Pathophysiological roles of the ligase that generate M1-linked chain and mechanism underlying M1-chain generation was studied. Then, I found that 1. M1-chains are essential for the function of B lymphocytes, 2.the ligase (LUBAC) and de ubiquitinating enzymes (OTULIN and CYLD) that are specific for M1-linked chains always form complex and tune strength of NF-kappaB activation elicited by M1-chains, M1-chains are involved in the oncogenesis of B cell lymphomas, and Aspergillus, an opportunistic pathogen for pneumonia, infects to lung by suppressing the generation of M1-chains.

Research Products

• [Journal Article] HTLV-1 Tax induces formation of the active macromolecular IKK complex by generating Lys63- and Met1-linked hybrid polyubiquitin chains. (2017)
  • Author(s): Shibata, Y., Tokunaga, F., Goto, E., Komatsu, G., Gohda, J., Saeki, Y., Tanaka, K., Takahashi, H., Sawasaki, T., Inoue, S., Oshiumi, H., Seya, T., Nakano, H., Tanaka, Y., Iwai, K., and Inoue, J.I.
  • Journal Title: PLoS Pathog. Volume: 13 Pages: e1006162
  • DOI: doi: 10.1371/journal.ppat.1006162
  • Peer Reviewed
• [Journal Article] Linear ubiquitination is involved in the pathogenesis of optineurin-associated amyotrophic lateral sclerosis. (2016)
  • Author(s): Nakazawa, S., Oikawa, D., Ishii, R., Ayaki, T., Takahashi, H., Takeda, H., Ishitani, R., Kamei, K., Takeyoshi, I., Kawakami, H., Iwai, K., Hatada, I., Sawasaki, T., Ito, H., Nureki, O., and Tokunaga, F.
  • Journal Title: Nat Commun. Volume: 7 Pages: 12547
  • DOI: doi: 10.1038/ncomms12547
  • Peer Reviewed
• [Journal Article] Survival of mature T cells depends on signaling through HOIP. (2016)
  • Author(s): Okamura, K., Kitamura, A., Sasaki, Y., Chung, D.H., Kagami, S., Iwai, K., and Yasutomo, K.
  • Journal Title: Sci. Rep. Volume: 6 Pages: 36135
  • DOI: doi: 10.1038/srep36135
  • Peer Reviewed
• [Journal Article] Differential involvement of the NZF domains of SHARPIN and HOIL-1L in LUBAC-mediated cell death protection. (2016)
  • Author(s): Shimizu, S., Fujita, H., Sasaki, Y., Tsuruyama, T., Fukuda, K., and Iwai, K.
  • Journal Title: Mol. Cell. Biol. Volume: 36 Pages: 1569-1583
  • DOI: doi:10.1128/MCB.01049-15
  • Peer Reviewed
• [Journal Article] LUBAC Formation Is Impaired in the Livers of Mice with MCD-Dependent Nonalcoholic Steatohepatitis. (2015)
  • Author(s): Matsunaga, Y., Nakatsu, Y., Fukushima, T., Okubo, H., Iwashita, M., Sakoda, H., Fujishiro, M., Yamamotoya, T., Kushiyama, A., Takahashi, S., Tsuchiya, Y., Kamata, H., Tokunaga, F., Iwai, K., and Asano, T.
  • Journal Title: Mediators Inflamm. Volume: 1 Pages: 125380
  • DOI: doi: 10.1155/2015/125380.
  • Peer Reviewed
• [Journal Article] CYLD and the NEMO zinc finger regulate tumor necrosis factor signaling and early embryogenesis. (2015)
  • Author(s): Zhao, Y., Ma, C. A., Wu, L., Iwai, K., Ashwell, J. D., Oltz, E. M., Ballard, D. W., and Jain, A.
  • Journal Title: J. Biol. Chem. Volume: 290 Pages: 22076-22084
  • DOI: doi: 10.1074/jbc.M115.658096
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The Structural differences between a glycoprotein specific F-Box protein Fbs1 and its homologous protein FBG3. (2015)
  • Author(s): Kumanomidou, T., Nishio, K., Takagi, K., Nakagawa, T., Suzuki, A., Yamane, T., Tokunaga, F., Iwai, K., Murakami, A., Yoshida, Y., Tanaka, K., and Mizushima, T.
  • Journal Title: PLoS One Volume: 10 Pages: e0140366
  • DOI: doi: 10.1371/journal.pone.0140366
  • Peer Reviewed
• [Journal Article] Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation. (2015)
  • Author(s): Bowman, J., Rodgers, M.A., Shi, M., Amatya, R., Hostager, B., Iwai, K., Gao, S.J., and Jung, J.U.
  • Journal Title: MBio. Volume: 6 Pages: e01777-15
  • DOI: doi: 10.1128/mBio.01777-15
  • Peer Reviewed / Int'l Joint Research
• [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: 393 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 / Open Access
• [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: doi: 10.1111/gtc.12128.
  • Peer Reviewed
• [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.
  • Peer Reviewed
• [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
  • 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: doi:10.1038/emboj.2013.184
  • Peer Reviewed
• [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.
  • 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: 641-652
  • DOI: doi: 10.1074/jbc.M112.347195.
  • 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: doi: 10.1016/j.chom.2012.06.009.
  • Peer Reviewed
• [Journal Article] Specific recognition of linear polyubiquitin by A20 zinc finger 7 is involved in NF-κB regulation. (2012)
  • Author(s): Tokunaga, F.
  • Journal Title: EMBO J. Volume: 31 Pages: 3856-3870
  • DOI: doi: 10.1038/emboj.2012.241.
  • 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: 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
  • Year and Date: 2016-12-06 – 2016-12-06
  • Int'l Joint Research
• [Presentation] Differential involvement of subunits of LUBAC ubiquitin ligase in signalling and cell death. (2015)
  • Author(s): Shimizu, S., Fujita, H., Sasaki, Y., and Iwai, K.
  • Organizer: EMBO Conference “Ubiquitin and ubiquitin-like modifiers: From molecular mechanisms to human diseases”
  • Place of Presentation: Cavtat, Croatia
  • Year and Date: 2015-09-18 – 2015-09-22
  • Int'l Joint Research
• [Presentation] Linear ubiquitin chains: NF-kappaB activation, cell death, and cancer. (2015)
  • Author(s): Iwai, K.
  • Organizer: International Symposium on Ubiquitin and Diseases.
  • Place of Presentation: Zhangjiajie, China
  • Year and Date: 2015-06-14 – 2015-06-19
  • Int'l Joint Research / Invited
• [Presentation] Linear ubiquitin chains: a new regulator of NF-kappaB 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 – 2015-06-13
  • Int'l Joint Research / Invited
• [Presentation] LUBAC-mediated linear ubiquitination by a virulence factor of Aspergillus, gliotoxin. (2015)
  • Author(s): Sakamoto, H., Egashira, S., Okabe, T., Nagano, T., and Iwai, K.
  • Organizer: Cold Spring Harbor Laboratory meeting “The Ubiquitin Family”
  • Place of Presentation: Cold Spring Harbor, NY, USA
  • Year and Date: 2015-04-21 – 2015-04-25
  • Int'l Joint Research
• [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
  • 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: 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
  • Invited
• [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
  • 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 – 2012-11-23
  • 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 – 2012-09-22
  • 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 – 2012-07-25
  • Invited
• [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/