Development of regulators of the LUBAC ubiquitin ligase that modulate NF-kappaB activation

• Project/Area Number: 24659136
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: General medical chemistry
• Research Institution: Kyoto University
• Principal Investigator: IWAI Kazuhiro 京都大学, 医学(系)研究科(研究院), 教授 (60252459)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 細胞内シグナル伝達 / シグナル伝達 / 直鎖状ポリユビキチン鎖 / 慢性皮膚炎 / NF-kappaB / 直鎖状ポリユビキチン鎖生成阻害剤

Research Abstract

NF-kappaB is a family of a transcription factor that involves in various biologcal phenomena including inflammation, immune responses, and cell survival. Abnormal activation NF-kappaB is also known to be related to the pathogenesis of various diseases. Thus, regulation of NF-kappaB is a suitable target of drugs for those diseases. Since we have identified LUBAC-mediated linear polyubiquitination is involved in NF-kappaB activation, we tried to develop the agents that up-regulate or inhibit LUBAC's ligase activity. We then identified a small chemical that inhibits LUBAC-mediated linear polyubiquitination and NF-kappaB actvation. Also, we found that interferon-gamma increases the amount of LUBAC and enhances NF-kappaB actvation.

Research Products

• [Journal Article] IFN-γor IFN-αameliorates 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
• [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 Issue: 3 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 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 Issue: 7 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 Issue: 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 Issue: 18 Pages: 2463-2476
  • 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): Naonobu Fujita et al.
  • Journal Title: J. Cell Biol. Volume: 203 Issue: 1 Pages: 115-128
  • DOI: 10.1083/jcb.201304188
  • Peer Reviewed / Open Access
• [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] Linear ubiquitination: a novel NF-κB regulatory mechanism for inflammatory and immune responses by the LUBAC ubiquitin ligase complex. (2012)
  • Author(s): Tokunaga, F,
  • Journal Title: Endocr. J. Volume: 59 Pages: 641-652
  • 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
• [Presentation] Increased redox-active iron induces mitochondrial damage that recruits Parkin. (2014)
  • Author(s): Iwai, K.
  • 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
  • Invited
• [Presentation] Linear polyubiquitination : a new regulator of NF-B activation (2013)
  • Author(s): Iwai, K
  • Organizer: The 38^<th> 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 (Invited)
  • Year and Date: 2013-07-07
• [Presentation] Linear polyubiquitination : a new regulator of NF-κB activation (2013)
  • Author(s): Iwai, K
  • Organizer: The 35^<th> Naito Conference"The Ubiquitin-Proteasome System : From Basic Mechanisms to Pathophysiological Roles"
  • Place of Presentation: Sapporo, Japan (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
  • Invited
• [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
  • 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.
• [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] Linear polyubiquitination: A crucial regulator of NF-κB signalling. (2012)
  • Author(s): Fujita, H.
  • Organizer: ZOMESVII conference
  • Place of Presentation: Munich Germany
  • Invited
• [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/