Elucidation of the regulatory mechanisms for balancing TLR7 and TLR9 responses by UNC93b1

• Project/Area Number: 21590528
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• Research Institution: The University of Tokyo
• Principal Investigator: SAITOH Shin-ichiroh 東京大学, 医科学研究所, 助教 (90361625)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2011: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2009: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: Toll-like receptor / 核酸認識 / ノックインマウス / LC-Ms/Ms解析 / TLR7 / TLR9 / 自然免疫 / 自己免疫疾患 / Toll-like Receptor / Unc93b1 / UNC93b1 / LC-MS / MS解析 / Yeast Two Hybrid

Research Abstract

We revealed that we have a mechanism for balancing TLR9 response as a DNA sensor and TLR7 response as a RNA sensor. We identified the PDZ binding domain in N terminal region of UNC93b1 regulating the balance. We established knock-in mice for disrupting the PDZ binding domain by single amino-acid substitution. TLR7 response significantly increases and TLR9 response decreases in the Knock-in mice. Around 75% of the Knock-in mice died within a year. The mice have systemic inflammation with splenomegaly. TLR7 knockout and UNC93b1 knock-in mice are no phenotype. This result indicates that TLR7 plays an important role for the systemic inflammation. We revealed the importance of negative regulatory mechanism via PDZ binding domain in UNC93b1 in vivo. We also identified a functional UNC93b1 binding protein to regulate TLR7 and TLR9 responses.

Research Products

• [Journal Article] Unc93B1 restricts systemic lethal inflammation by orchestrating TLR7-and TLR9-trafficking (2011)
  • Author(s): Fukui R, Saitoh S, Kanno A, Onji M, Shibata T, Ito A, Onji M, Matsumoto M, Akira S, YoshidaN, & Miyake K
  • Journal Title: Immunity Volume: 35 Pages: 69-81
• [Journal Article] Unc93B1 restricts systemic lethal inflammation by orchestrating Toll-like Receptor 7 and 9-trafficking (2011)
  • Author(s): 福井竜太郎、齋藤伸一郎, 他
  • Journal Title: Immunity Volume: 35 Pages: 68-81
  • Peer Reviewed
• [Journal Article] Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA-but against RNA-sensing (2009)
  • Author(s): Fukui R, Saitoh S, Matsumoto F, Kozuka-Hata H, Oyama M, Tabeta K, Beutler B, & Miyake K
  • Journal Title: J Exp Med Volume: 206 Pages: 1339-1350
• [Journal Article] Chaperons and transport proteins regulate TLR4 trafficking and activation. (2009)
  • Author(s): 齋藤伸一郎
  • Journal Title: Immunobiology 214 Pages: 594-600
• [Journal Article] Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing. (2009)
  • Author(s): 福井竜太郎, 齋藤伸一郎
  • Journal Title: The Journal of Experimental Medicine 206 Pages: 1339-1350
  • Peer Reviewed
• [Presentation] Unc93 homolog B1 restricts lethal homeostatic inflammation by regulating TLR7 and TLR9 reciprocally (2012)
  • Author(s): 福井竜太郎
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ
  • Year and Date: 2012-11-28
• [Presentation] 幕張メッセタイトル: TRAMの分子動態と抗原提示プラットホーム (2011)
  • Author(s): 谷村奈津子
  • Year and Date: 2011-11-28
• [Presentation] 幕張メッセタイトル: UNC93 homolog B1はTLR7とTLR9の反応性を相反的に制御し、致死的な自然炎症から生体を防御する (2011)
  • Author(s): 福井竜太郎
  • Year and Date: 2011-11-28
• [Presentation] UNC93b1を介したToll-like receptor(TLR) 7と9の制御 (2009)
  • Organizer: 第18回内毒素・LPS研究会
  • Place of Presentation: 東京大学
  • Year and Date: 2009-06-20
• [Presentation] UNC93b1を介したToll-like receptor (TLR)7と9の制御 (2009)
  • Author(s): 齋藤伸一郎
  • Organizer: 第18回内毒素LPS研究会
  • Place of Presentation: 東京大学
  • Year and Date: 2009-06-20
• [Book] Innate Immune Regulation and Cancer Immunotherapy (2011)
  • Author(s): Saitoh, S
  • Publisher: Toll-like Receptors and Their Regulatory Mechanisms
• [Book] Innate Immune Regulation and Cancer Immunotherapy (2011)
  • Author(s): 齋藤伸一郎
  • Total Pages: 11
  • Publisher: Springer
• [Book] Regulatory molecules required for nucleotide-sensing Toll-like receptors (2009)
  • Author(s): Saitoh S, & Miyake K
  • Total Pages: 227
  • Publisher: Immunol. Rev
• [Book] Chaperones and transportproteins regulate TLR4 trafficking and activation (2009)
  • Author(s): Saitoh S
  • Total Pages: 214
  • Publisher: Immunobiology
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/kanseniden/index.html
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/kanseniden/index.htlm
• [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,齊藤,伸一郎福井,竜太郎
  • Industrial Property Rights Holder: 三宅健介
  • Filing Date: 2010-08-10
• [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 齊藤伸一郎 福井竜太郎
  • Industrial Property Rights Holder: 三宅健介
  • Filing Date: 2010-08-10