Studying mechanisms controlling responsiveness of Toll-like Receptors

• Project/Area Number: 20390140
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: The University of Tokyo
• Principal Investigator: MIYAKE Kensuke The University of Tokyo, 医科学研究所, 教授 (60229812)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥20,020,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥4,620,000); Fiscal Year 2010: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2009: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2008: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
• Keywords: 自然免疫 / Toll様受容体 / 病原体センサー / Toll-like receptor / 病原体

Research Abstract

In the present study, we analyzed mechanisms regulating responsiveness of the Toll family of receptors. A variety of molecules are required for regulating TLR function. PRAT4A, e.g., is required for trafficking of cell surface TLRs from the ER to the cell surface. Unc93B1 is required for the trafficking of nucleic acid-sensing TLRs from the ER to the endolysosomes. Unc93B1 also has a role in balancing RNA-sensing TLR7 and DNA-sensing TLR9.

Research Products

• [Journal Article] Intracellular TLR4/MD-2 in macrophages senses Gram-negative bacteria and induces a unique set of LPS-dependent genes. (2011)
  • Author(s): Shibata T, Motoi Y, Tanimura N, Yamakawa N, Akashi-Takamura S, Miyake, K
  • Journal Title: Int.Immunol. in press
  • Peer Reviewed
• [Journal Article] Unc93B1 restricts systemic lethal inflammation by orchestrating TLR7- and TLR9-trafficking. (2011)
  • Author(s): Fukui R, Saitoh S-I, Kanno A, Onji M, Shibata T, Ito A, Onji M, Matsumoto M, Akira S, Yoshida N, Miyake K.
  • Journal Title: Immunity in press
  • Peer Reviewed
• [Journal Article] Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Tbll-like receptors and endo plasmic reticulum homeostasis. (2011)
  • Author(s): Hirai M, Kadowaki N, Kitawaki T, Fujita H, Takaori-Kondo A, Fukui R, Minke K, Maeda T, Kamihira S, Miyachi Y, Uchiya ma T.
  • Journal Title: BLOOD Volume: 117 Pages: 500-509
  • Peer Reviewed
• [Journal Article] Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells towards DNA- but against RNA-sensing. (2009)
  • Author(s): Fukui R, Saitoh S-I, Matsumoto F, Kozuka-Hara H, Oyama M, Tabeta K, Beutler B, *Miyake K.
  • Journal Title: J.Exp.Med. in press
  • Peer Reviewed
• [Journal Article] Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells towards DNA- but against RNA-sensing (2009)
  • Author(s): Fukui R, Saitoh S-I, Matsumoto F, Kozuka-Hara H, Oyama M, Tabeta K, Beutler B, *Miyake K
  • Journal Title: The Journal of Experimental Medicine 206 Pages: 1339-1350
  • Peer Reviewed
• [Journal Article] A single base mutation in the PRAT4A gene reveals differential interaction of PRAT4A with Toll-like receptors. (2008)
  • Author(s): Kiyokawa T, Akashi-Takamura S, Shibata T, Matsumoto F, Nishitani C, Kuroki Y, Seto Y, *Miyake K.
  • Journal Title: Int.Immunol. 20 Pages: 1407-1415
  • NAID: 10024357741
  • Peer Reviewed
• [Journal Article] Tonic B cell activation by Radioprotective105/MD-1 promotes disease progression in MRL/lpr mice. (2008)
  • Author(s): Kobayashi, T., K.Takahashi, Y.Nagai, T.Shibata, M.Otani, S.Izui, S.Akira, Y.Gotoh, H.Kiyono, *Miyake K
  • Journal Title: Int.Immunol. 20 Pages: 881-891
  • Peer Reviewed
• [Journal Article] Roles for LPS-dependent interaction and relocation of TLR4 and TRAM in TRIF-signaling. (2008)
  • Author(s): Tanimura N, Saitoh S, Matsumoto F, Akashi-Takamura S, *Miyake K.
  • Journal Title: Biochem Biophys Res Commun. 368 Pages: 94-99
  • Peer Reviewed
• [Journal Article] Cathepsins are required for Toll-like receptor 9 responses. (2008)
  • Author(s): Matsumoto F, Saitoh S, Fukui R, Kobayashi T, Tanimura N, Konno K, Kusumoto Y, Akashi-Takamura S, *Miyake K.
  • Journal Title: Biochem Biophys Res Commun. 367 Pages: 693-699
  • Peer Reviewed
• [Journal Article] Tonic B cell activation by Radioprotective105/MD-1 promotes disease progression in MRL/1pr mice (2008)
  • Author(s): Kobayashi, T., K.Takahashi, Y.Nagai, T.Shibata, M.Otani, S.Izui, S.Akira, Y.Gotoh, H.Kiyono, K.Miyake
  • Journal Title: International Immunology 20 Pages: 881-891
  • Peer Reviewed
• [Journal Article] A single base mutation in the PRAT4A gene reveals differential interaction of PRAT4A with Toll-like receptors (2008)
  • Author(s): Kiyokawa T, Akashi-Takamura S, Shibata T, Matsumoto F, Nishitani C, Kuroki Y, Seto Y, Miyake K.
  • Journal Title: International Immunology 20 Pages: 1407-1415
  • NAID: 10024357741
  • Peer Reviewed
• [Presentation] Roles for Unc93 homolog B1-dependent TLR7/9 balance in vivo (2010)
  • Author(s): 福井竜太郎
  • Organizer: 第14回国際免疫学会
  • Place of Presentation: 神戸ポートピアホテル
  • Year and Date: 2010-08-23
• [Presentation] Roles for Unc93 homolog Bl-dependent TLR7/TLR9 balance in vivo (2010)
  • Author(s): Fukui, et al.
  • Organizer: 第14回国際免疫学会
  • Place of Presentation: 神戸国際展示場
  • Year and Date: 2010-08-23
• [Presentation] Unc93 homolog B1はTLR7とTLR9の応答バランスを相反的に制御する (2009)
  • Author(s): 福井竜太郎
  • Organizer: 第39回日本免疫学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2009-12-04
• [Presentation] Unc93 homolog B1 regulates the balance of toll-like receptor 7 and toll-like receptor 9 responses reciprocally in dendritic cells (2009)
  • Author(s): 福井竜太郎
  • Organizer: Tri-Society Annual Conference
  • Place of Presentation: Lisbon congress center(リスボン、ポルトガル)
  • Year and Date: 2009-10-20
• [Presentation] Unc93B1はTLR7とTLR9の応答性を制御する (2008)
  • Author(s): 福井竜太郎
  • Organizer: 第38回日本免疫学会学術集会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2008-12-02
• [Presentation] A single base mutation in the PRAT4A gene reveals differential interaction of PRAT4A with Toll-like receptors (2008)
  • Author(s): Kiyokawa T, Akashi-Takamura S, Shibata T, Matsumoto F, Nishitani C, Kuroki Y, Seto Y, Miyake K.
  • Organizer: 日本免疫学会総会
  • Place of Presentation: 京都
  • Year and Date: 2008-12-02
• [Presentation] Detection of soluble PRAT4A (Protein Associated with Toll-likeReceptor4) by novel anti-PRAT4A monoclonal antibody (2008)
  • Author(s): 柴田琢磨
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 国立京都国際会館
• [Patent(Industrial Property Rights)] Unc93B1遺伝子改変マウスの確立とその応用 (2010)
  • Inventor(s): 三宅健介、斎藤伸一郎、福井竜太郎
  • Industrial Property Rights Holder: 東京大学
  • Filing Date: 2010-08-10
  • Overseas