Analysis of pathophysiology of LUBAC mediated NF-kappaB activation

• Project/Area Number: 22249008
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kyoto University (2012-2013); Osaka University (2010-2011)
• Principal Investigator: IWAI Kazuhiro 京都大学, 医学(系)研究科(研究院), 教授 (60252459)
• Project Period (FY): 2010-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥47,710,000 (Direct Cost: ¥36,700,000、Indirect Cost: ¥11,010,000); Fiscal Year 2012: ¥24,050,000 (Direct Cost: ¥18,500,000、Indirect Cost: ¥5,550,000); Fiscal Year 2011: ¥11,180,000 (Direct Cost: ¥8,600,000、Indirect Cost: ¥2,580,000); Fiscal Year 2010: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
• Keywords: 細胞内シグナル伝達 / 直鎖状ポリユビキチン鎖 / LUBAC / NF-kappaB / ユビキチン / アレルギー / 免疫異常 / NF-κB / 皮膚炎

Research Abstract

The LUBAC ubiquitin ligase activates NF-kappaB by generating linear polyubiquitin chains. Previously, we have identified HOIL-1L and HOIP as components of LUBAC. In this study, we identified SHARPIN as the other subunit of LUBAC. Cpdm mice, a spontaneous mutant mice that exhibit pleomorphic phenotypes including chronic dermatitis, lack SHARPIN. We found that destabilization of the other subunits of LUBAC and lack of SHARPIN are causative for the phenotypes of cpdm mice. We also examined the roles of LUBAC mediated linear polyubiquitination in B cells and found that LUBAC's ligase activity is necessary for B1 cell development and antibody responses to thymus-dependent and thymus-independent-II antigens.

Research Products

• [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
• [Journal Article] Activation of nuclear factor-kappa B by linear ubiquitin chain assembly complex contributes to lung metastasis of osteosarcoma cells (2012)
  • Author(s): Tomonaga, M., Hashimoto, N., Tokunaga, F., Onishi, M., Myoui, A., Yoshikawa, H. and Iwai, K
  • Journal Title: Int. J. Oncol. Volume: 40 Pages: 409-417
• [Journal Article] Non-canonical UBA–UBL interaction mediates formation of linear ubiquitin chain assembly complex (2012)
  • Author(s): Yagi, H., Ishimoto, K., Takeshi Hiromoto, T., Fujita, H., Mizushima, T., Uekusa, Y., Yagi-Utsumi, M., Kurimoto, E., Noda, M., Uchiyama, S., Tokunaga, F., Iwai, K. (Correspondence author) and Kato, K
  • Journal Title: EMBO Rep. Volume: 13 Pages: 462-468
• [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., Tokunaga, F., Ikeda, F., Goto, E., Iwai, K. and Dikic, I
  • Journal Title: J. Biol. Chem. Volume: 287(28) Pages: 23626-23634
• [Journal Article] Linear ubiquitination of NEMO negatively regulates the interferon antiviral response through disruption of the MAVS-TRAF3 complex (2012)
  • Author(s): Belgnaoui, S.M., Paz, S., Samuel, S., Goulet, M.L., Sun, Q., Kikkert, M., Iwai, K., Dikic, I., Hiscott, J. and Lin, R
  • Journal Title: Cell Host Microbe. Volume: 12(2) Pages: 211-222
• [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. and Nureki, O
  • Journal Title: EMBO J. Volume: 31(19) Pages: 3856-3870
• [Journal Article] Diverse ubiquitin signaling in NF-κB activation. (2012)
  • Author(s): Iwai, K.
  • Journal Title: Trends Cell Biol. Volume: 22 Issue: 7 Pages: 355-364
  • DOI: 10.1016/j.tcb.2012.04.001
  • 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] 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 Issue: 2 Pages: 211-222
  • 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, 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] 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] Linear ubiquitin assembly complex negatively regulates RIG-I- and TRIM25-mediated type-I interferon induction (2011)
  • Author(s): Inn, K.-S., Gack, M. U. Tokunaga, F., Shi, M., Wong, L.-Y., Iwai, K. (corresponding author) and Jung, J. U
  • Journal Title: Molecular Cell Volume: 41 Pages: 354-365
• [Journal Article] SHARPIN is a component of the NF-B activating linear ubiquitin chain assembly complex (2011)
  • Author(s): Tokunaga, F., Nakagawa, T., Nakahara, M., Saeki, Y., Taniguchi, M., Sataka, S.-I., Tanaka, K., Nakano, H., and Iwai, K
  • Journal Title: Nature Volume: 471 Pages: 633-636
• [Journal Article] SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis (2011)
  • Author(s): Ikeda, F., Deribe, Y. L., Skånland, S.S., Stieglitz, B., Grabbe, C., Franz-Wachtel, M., van Wijk, S.J.L., Goswami, P., Nagy, V., Terzic, J., Tokunaga, F., Androulidaki, A., Nakagawa, T., Pasparakis, M., Iwai, K., Sundberg, J.P., Rittinger, K., Schaefer, L., Macek, B. and Dikic, I
  • Journal Title: Nature Volume: 471 Pages: 637-641
• [Journal Article] LUBAC regulates NF-κB activation upon genotoxic stress by promoting linear ubiquitination of NEMO (2011)
  • Author(s): Niu, J., Shi, Y., Iwai, K. and Wu, Z.-H
  • Journal Title: EMBO J. Volume: 30 Pages: 3741-3753
• [Journal Article] Specific Recognition of Linear Ubiquitin Chains by the HOIL-1L NZF domain (2011)
  • Author(s): Sato, Y., Fujita, H., Yoshikawa, A.,Yamashita, M., Yamagata, A., Kaiser, S. E., Iwai, K., and Fukai, S
  • Journal Title: Proc. Natl. Acad. Sci. Volume: USA 108 Pages: 20520-20525
• [Journal Article] LUBAC regulates NF-κB activation upon genotoxic stress by promoting linear ub iquitination of NEMO (2011)
  • Author(s): Niu, J., Shi, Y., Iwai, K., Wu, Z.-H.
  • Journal Title: EMBO J Volume: 30(18) Issue: 18 Pages: 3741-3753
  • DOI: 10.1038/emboj.2011.264
  • Peer Reviewed
• [Journal Article] Specific recognition of linear ubiquitin chains by the Npl4 zinc finger(NZF) domain of the HOIL-1L subunit of the linear ubiquitin chain assembly complex (2011)
  • Author(s): Sato, Y., Fujita, H., Yoshikawa, A., Yamashita, M., Yamagata, A., Kaiser, S. E., Iwai, K., Fukai, S
  • Journal Title: Proceedings of National Academy of Science United States of America Volume: 108巻 Issue: 51 Pages: 20520-20525
  • DOI: 10.1073/pnas.1109088108
  • Peer Reviewed
• [Journal Article] Linear ubiquitin assembly complex negatively regulates RIG-I- and TRIM25-mediated type-1 interferon induction (2011)
  • Author(s): Inn, K.-S., Gack, M.U., Tokunaga, F., Shi, M., Wong, L.-Y., Iwai, K.,(責任著者), Jung, J.U.
  • Journal Title: Molecular Cell Volume: 41 Pages: 354-365
  • 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., Sataka, S.-I., Tanaka, K., Nakano, H., Iwai, K.
  • Journal Title: Nature Volume: 471 Pages: 633-636
  • Peer Reviewed
• [Presentation] Linear polyubiquitination : A crucial regulator of NF-B signaling (2012)
  • Author(s): Iwai, K., Fujita, H., Nakahara, M., Sano, S. and Tokunaga. F
  • Organizer: Keystone Symposium"NF-B signaling and Biology : From Bench to Bedside"and"Ubiquitin Signaling"
  • Place of Presentation: Whistler, Canada
  • Invited
• [Presentation] Linear polyubiquitination : a regulator of NF-B activation (2012)
  • Author(s): Iwai, K
  • Organizer: 2012 FASEB Summer Research Conferences"Ubiquitin & Cellular Regulation"
  • Place of Presentation: Saxtons River, Vermont, USA
  • Invited
• [Presentation] Mechanism underlying generation of linear polyubiquitin chains (2012)
  • Author(s): Iwai, K
  • Organizer: 4th Annual Ubiquitin Drug Discovery & Diagnostics Conference
  • Place of Presentation: Four Seasons Hotel, Philadelphia, USA
  • Invited
• [Presentation] Linear polyubiquitination : A crucial regulator of NF-B signalling (2012)
  • Author(s): Fujita, H., Sasaki, Y., Nakahara, M. Iwai, K
  • Organizer: A crucial regulator of NF-B signalling ZOMESVII conference
  • Place of Presentation: Munich Germany
  • Invited
• [Presentation] Linear polyubiquitination : A crucial regulator of NF-B 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
  • Invited
• [Presentation] Linear polyubiquitination: a regulator of NF-κB activation. (2012)
  • Author(s): Iwai, K.
  • Organizer: 2012 FASEB Summer Research Conferences “Ubiquitin & Cellular Regulation”
  • Place of Presentation: Vermont, USA
  • 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
  • Invited
• [Presentation] Linear polyubiquitination: A crucial regulator of NF-κB signalling. (2012)
  • Author(s): Fujita, H.
  • Organizer: ZOMESVII conference
  • Place of Presentation: Munich Germany
  • 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
  • Invited
• [Presentation] Linear polyubiquitination : A new regulator of NF-κB activation (2011)
  • Author(s): Iwai, K.
  • Organizer: The EMBO Conference "Ubiquitin and Ubiquitin-like Modifiers From functional modules to system biology"
  • Place of Presentation: Cavtat(クロアチア)(招待講演)
  • Year and Date: 2011-09-25
• [Presentation] Linear polyubiquitination : A new regulator of NF-B activation (2011)
  • Author(s): Iwai, K
  • Organizer: The EMBO Conference"Ubiquitin and Ubiquitin-like Modifiers : From functional modules to system biology"
  • Place of Presentation: Cavtat, Croatia
  • Invited
• [Presentation] Linear polyubiquitination : a new regulator of NF-B signaling (2010)
  • Author(s): Iwai, K
  • Organizer: 2010 FASEB Summer Research Conferences"Ubiquitin and Cellular Regulation"
  • Place of Presentation: Saxtons River, Vermont, USA
  • Invited
• [Presentation] Dissection of intracellular heme transport mechanism using a baker's yeast, Saccharomyces cerevisiae (2010)
  • Author(s): Ueta, R. and Iwai, K
  • Organizer: JSH International Symposium 2010 in Akita, Seven Wonders of Erythropoiesis
  • Place of Presentation: Akita, Japan
  • Invited
• [Presentation] Linear polyubiquitination : a new regulator of NF-B signaling. Banbury Center meetings (2010)
  • Author(s): Iwai, K
  • Organizer: SIGNALING THROUGH UBIQUITIN
  • Place of Presentation: The Banbury Center, Cold Spring Harbor Laboratory, New York, USA
  • Invited
• [Presentation] Linear polyubiquitination : a new regulator of NF-κB signaling (2010)
  • Author(s): Iwai, K.
  • Organizer: FASEB Summer Research Conferences "Ubiquitin and Cellular Regulation"
  • Place of Presentation: Saxtons River, Vermont, USA(招待講演)
• [Book] LUBAC, a novel ubiquitin ligase for linear ubiquitination, is crucial for inflammation and immune responses (2012)
  • Author(s): Tokunaga, F., and Iwai, K
  • Publisher: Microbes Infect.
• [Book] Generation and physiological roles of linear ubiquitin chains (2012)
  • Author(s): Walczak, H., Iwai, K., and Dikic, I
  • Publisher: BMC Biol.
• [Book] Diverse ubiquitin signaling in NF-B activation (2012)
  • Author(s): Iwai, K
  • Publisher: Trends Cell Biol.
• [Book] A novel NF-κB regulatory mechanism for inflammatory and immune responses by the LUBAC ubiquitin ligase complex Endocr J (2012)
  • Author(s): Tokunaga, F. and Iwai K
  • Publisher: Linear ubiquitination
• [Book] Methods Mol Biol.担当分Synthesis and analysis of linear ubiquitin chains. 229-238ページ (2012)
  • Author(s): Iwai K.
  • Total Pages: 661
  • Publisher: Humana Press
• [Book] Linear polyubiquitin chains : a new modifier involved in NF-B activation and chronic inflammation including dermatitis (2011)
  • Author(s): Iwai, K
  • Publisher: -Extra View- Cell Cycle
• [Book] Conjugation and Deconjugation of Ubiquitin Family Modifiers (2010)
  • Author(s): Iwai K.
  • Total Pages: 272
  • Publisher: Groettrup, M.eds Landes Biosciences
• [Remarks]
  • URL: http://www.mcp.med.kyoto-u.ac.jp/
• [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/
• [Remarks]
  • URL: http://www.cellbio.med.osaka-u.ac.jp/
• [Remarks]
  • URL: http://www.cellbio.med.osaka-u.ac.jp/
• [Patent(Industrial Property Rights)] 特許 (2012)
  • Inventor(s): 岩井一宏
  • Industrial Property Rights Holder: 大阪大学
  • Industrial Property Number: 2011-525944
  • Filing Date: 2012-02-20
• [Patent(Industrial Property Rights)] 新規なユビキチンリガーゼおよびその利用 (2010)
  • Inventor(s): 岩井一宏
  • Industrial Property Rights Holder: 大阪大学
  • Filing Date: 2010-08-06
  • Overseas