Toll like receptors; their endogenous ligands and mechanism regulating their activities

• Project Area: Homeostatic inflammation: Molecular basis and dysregulation
• Project/Area Number: 21117002
• 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: The University of Tokyo
• Principal Investigator: MIYAKE Kensuke 東京大学, 医科学研究所, 教授 (60229812)
• Co-Investigator(Kenkyū-buntansha): OHTO Umeharu 東京大学, 薬学研究科, 助教 (90451856) ; NAKANISHI Hiroki 秋田大学, 生体情報研究センター, 助教 (10466740)
• Co-Investigator(Renkei-kenkyūsha): TAKAMURA Sachiko 東京大学, 医科学研究所, 助教 (00325599) ; SITOH Shin-ichiroh 東京大学, 医科学研究所, 助教 (90361625)
• Project Period (FY): 2009-07-23 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥245,440,000 (Direct Cost: ¥188,800,000、Indirect Cost: ¥56,640,000); Fiscal Year 2013: ¥49,530,000 (Direct Cost: ¥38,100,000、Indirect Cost: ¥11,430,000); Fiscal Year 2012: ¥48,490,000 (Direct Cost: ¥37,300,000、Indirect Cost: ¥11,190,000); Fiscal Year 2011: ¥47,450,000 (Direct Cost: ¥36,500,000、Indirect Cost: ¥10,950,000); Fiscal Year 2010: ¥48,490,000 (Direct Cost: ¥37,300,000、Indirect Cost: ¥11,190,000); Fiscal Year 2009: ¥51,480,000 (Direct Cost: ¥39,600,000、Indirect Cost: ¥11,880,000)
• Keywords: Toll様受容体 / 自然免疫 / 自然得免疫 / 病源体センサー / 病原体センサー

Research Abstract

Toll-like receptors (TLR) sense not only microbial products, but also self-derived endogenous products. We here searched endogenous ligands such as lipids and nucleic acids. We succeeded in solving the structure of TLR8. The structure predicts endogenous ligands to TLR8. Those ligands were studied by in vitro functional analyses. We also studied mechanisms regulating TLRs in the steady state. Unc93B1 controls TLR trafficking. We have found that Unc93B1 also has a role in regulating TLR7 responses in the steady state. These results suggest that TLRs steadily respond to endogenous ligands and their activities are tightly regulated.

Research Products

• [Journal Article] UNC93B1 is essential for the plasma membrane localization and signaling of Toll-like receptor 5 (2014)
  • Author(s): Huh JW, Shibata T, Hwang M, Kwon EH, Jang MS, Fukui R, Kanno K, Jung DJ, Jang MH, Miyake K, and Kim YM
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 111 Issue: 19 Pages: 7072-7077
  • DOI: 10.1073/pnas.1322838111
  • Peer Reviewed
• [Journal Article] The attenuated inflammation of MPL is due to the lack of CD14-dependent tight dimerization of TLR4/MD2 complex at the plasma membrane (2013)
  • Author(s): Tanimura N, Saitoh S, Ohto U, Akashi-Takamura A, Fujimoto Y, Fukase K, Shimizu T, Miyake K
  • Journal Title: Int. Immunol. Volume: 26 Issue: 6 Pages: 307-314
  • DOI: 10.1093/intimm/dxt071
  • Peer Reviewed
• [Journal Article] An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing (2013)
  • Author(s): Onji M, Kanno A, Saitoh S, Fukui R, Motoi Y, Shibata T, Matsumoto F, Lamichhane A, Sato S, Kiyono H, Yamamoto K, Miyake K
  • Journal Title: Nat. Commun. Volume: 4 Issue: 1 Pages: 1949-1949
  • DOI: 10.1038/ncomms2949
  • NAID: 120005359107
  • Peer Reviewed
• [Journal Article] Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands (2013)
  • Author(s): Tanji H, Ohto U, Shibata T, Miyake K, Shimizu T
  • Journal Title: Science Volume: 339 Issue: 6126 Pages: 1426-1429
  • DOI: 10.1126/science.1229159
  • Peer Reviewed
• [Journal Article] Human TLR4 polymorphism D299G/T399I alters TLR4/MD-2 conformation and response to a weak ligand monophosphoryl lipid A (2013)
  • Author(s): Yamakawa N, Ohto U, Akashi-Takamura S, Takahashi K, Saitoh SI, Tanimura N, Suganami T, Ogawa Y, Shibata T, Shimizu T, Miyake K
  • Journal Title: Int Immunol. Volume: 25 Pages: 45-52
• [Journal Article] Endocytosis-free DNA sensing by cell surface TLR9 in neutrophils: Rapid defense with autoimmune risks (2013)
  • Author(s): Miyake K, Onji M
  • Journal Title: Eur J Immunol Volume: 43 Issue: 8 Pages: 2006-2009
  • DOI: 10.1002/eji.201343882
  • Peer Reviewed
• [Journal Article] Human TLR4 polymorphism D299G/T399I alters TLR4/MD-2 conformation and response to a weak ligand monophosphoryl lipid A (2013)
  • Author(s): N. Yamakawa, U. Ohto, S. Akashi-Takamura, K. Takahashi, SI. Saitoh, N. Tanimura, T. Suganami, Y. Ogawa, T. Shibata, T. Shimizu, K. Miyake
  • Journal Title: Int. Immunol. Volume: 25 Issue: 1 Pages: 45-52
  • DOI: 10.1093/intimm/dxs084
  • Peer Reviewed
• [Journal Article] Essential role for Toll-like receptor 7 (TLR7)-unique cysteines in intramolecular disulfide bond, proteolytic cleavage, and RNA-sensing (2013)
  • Author(s): Kanno A, Yamamoto C, Onji M, Fukui R, Saitoh SI, Motoi Y, Shibata T, Matsumoto F, Muta T, Miyake K
  • Journal Title: Int Immunol. Volume: 25 Issue: 7 Pages: 413-422
  • DOI: 10.1093/intimm/dxt007
  • Peer Reviewed
• [Journal Article] TLR4-MD-2 complex is negatively regulated by an endogenous ligand, globotetraosylceramide in vascular endothelial cells. (2013)
  • Author(s): Kondo, Y., Tokuda, N., Nishitani, C., Ohto, U., Akashi-TakKondo, Y., Tokuda, N., Nishitani, C., Ohto, U., Akashi-Takamura, S., Ito, Y., Uchikawa, M., Kuroki, Y., Miyake, K., Zhang, Q., Furukawa, K., Furukawa, K
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 110 Issue: 12 Pages: 4714-4719
  • DOI: 10.1073/pnas.1218508110
  • Peer Reviewed
• [Journal Article] PRAT4A-dependent expression of cell surface TLR5 on neutrophils, classical monocytes and dendritic cells (2012)
  • Author(s): Shibata T, Takemura N, Motoi Y, Goto Y, Karuppuchamy T, Izawa K, Li X, Akashi-Takamura S, Tanimura N, Kunisawa J, Kiyono H, Akira S, Kitamura T, Kitaura J, Uematsu S, Miyake K
  • Journal Title: Int Immunol. Volume: 24 Issue: 10 Pages: 613-623
  • DOI: 10.1093/intimm/dxs068
  • Peer Reviewed
• [Journal Article] Structural analyses of human Toll-like receptor polymorphisms D299G and T399I (2012)
  • Author(s): Ohto U, Yamakawa N, Akashi-Takamura S, Miyake K, Shimizu T
  • Journal Title: J Biol Chem. Volume: 287 Issue: 48 Pages: 40611-40617
  • DOI: 10.1074/jbc.m112.404608
  • Peer Reviewed
• [Journal Article] Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2 (2012)
  • Author(s): Ohto U, Fukase K, Miyake K, Shimizu T
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 109 Issue: 19 Pages: 7421-7426
  • DOI: 10.1073/pnas.1201193109
  • Peer Reviewed
• [Journal Article] The RP105/MD-1 complex is indispensable for TLR4/MD-2-dependent proliferation and IgM-secreting plasma cell differentiation of marginal zone B cells (2012)
  • Author(s): Yoshinori Nagai
  • Journal Title: International Immunology Volume: (in press) Issue: 6 Pages: 389-400
  • DOI: 10.1093/intimm/dxs040
  • Peer Reviewed
• [Journal Article] The Radioprotective 105/MD-1 complex contributes to diet-induced obesity and adipose tissue inflammation (2012)
  • Author(s): Y. Watanabe, T. Nakamura, S. Ishikawa, S. Fujisaka, I. Usui, K. Tsuneyama, Y. Ichihara, T. Wada, Y. Hirata, T. Suganami, H. Izaki, S. Akira, K. Miyake, H. Kanayama, M. Shimabukuro, M. Sata, T. Sasaoka, Y. Ogawa, K. Tobe, K. Takatsu, Y. Nagai
  • Journal Title: Diabetes Volume: 61 Issue: 5 Pages: 1199-1209
  • DOI: 10.2337/db11-1182
  • Peer Reviewed
• [Journal Article] Glycyrrhizin and isoliquiritigenin suppress the LPS sensor Toll-like receptor 4/MD-2 complex signaling in a different manner (2012)
  • Author(s): Honda, H., et al
  • Journal Title: Journal of Leukocyte Biology Volume: (in press) Issue: 6 Pages: 967-976
  • DOI: 10.1189/jlb.0112038
  • Peer Reviewed
• [Journal Article] Saturated fatty acid and TLR signaling link β cell dysfunction and islet inflammation. (2012)
  • Author(s): Eguchi K, Manabe I, Oishi-Tanaka Y, Ohsugi M, Kono N, Ogata F, Yagi N, Ohto U, Kimoto M, Miyake K, Tobe K, Arai H, Kadowaki T, Nagai R
  • Journal Title: Cell Metab. Volume: 15 Issue: 4 Pages: 518-533
  • DOI: 10.1016/j.cmet.2012.01.023
  • Peer Reviewed
• [Journal Article] Peroxiredoxin family proteins are key initiators of post-ischemic inflammation in the brain (2012)
  • Author(s): Shichita T
  • Journal Title: Nature Medicine Volume: 18 Issue: 6 Pages: 911-917
  • DOI: 10.1038/nm.2749
  • Peer Reviewed
• [Journal Article] Coagulation Factor X Activates Innate Immunity to Human Species C Adenovirus. (2012)
  • Author(s): Doronin K.
  • Journal Title: Science. Volume: 6108 Issue: 6108 Pages: 795-8
  • DOI: 10.1126/science.1226625
  • 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 Volume: 35 Pages: 69-81
• [Journal Article] Unc93B1 restricts systemic lethal inflammation by orchestrating Toll-like receptor 7 and 9 trafficking (2011)
  • Author(s): Fukui R
  • Journal Title: Immunity Volume: 35 Issue: 1 Pages: 69-81
  • DOI: 10.1016/j.immuni.2011.05.010
  • Peer Reviewed
• [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. Volume: 23 Issue: 8 Pages: 503-510
  • DOI: 10.1093/intimm/dxr044
  • Peer Reviewed
• [Journal Article] Novel dimer organization of the TLR family as revealed by the crystal structures of mouse and human RP105/MD-1 complex (2011)
  • Author(s): Ohto U, Miyake K, Shimizu T
  • Journal Title: J.Mol.Biol. Volume: 413 Issue: 4 Pages: 815-825
  • DOI: 10.1016/j.jmb.2011.09.020
  • Peer Reviewed
• [Journal Article] Bortezomib suppresses function and survival of plasmacytoid dendritic cells by targeting intracellular trafficking of Toll-like receptors and endoplasmic reticulum homeostasis. (2011)
  • Author(s): Hirai M, Kadowaki N, Kitawaki T, Fujita H, Takaori-Kondo A, Fukui R, Miyake K, Maeda T, Kamihira S, Miyachi Y, Uchiyama T.
  • Journal Title: BLOOD Volume: 117 Pages: 500-509
  • Peer Reviewed
• [Journal Article] Crystal structure of mouse MD-1 with endogenous phospholipid bound in its cavity (2010)
  • Author(s): Harada, H., Ohto, U., Satow, Y.
  • Journal Title: J.Mol.Biol. Volume: 400 Pages: 838-846
  • 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, and Miyake K
  • Journal Title: J. Exp. Med. Volume: 206 Pages: 1339-1350
• [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 Volume: 206 Pages: 1339-1350
  • Peer Reviewed
• [Presentation] Nucleic acid-sensing Toll-like receptors : their recognition and regulation (2013)
  • Organizer: The 21th international symposium of macrophage molecular and cellular biology (MMCB)2013
  • Place of Presentation: Tokyo, Japan
• [Presentation] TLR logistics by Unc93B1 as a mechanism regulating autoimmunity (2013)
  • Organizer: American Association of Immunologists (AAI) annual meeting 2013
  • Place of Presentation: Honolulu, USA
• [Presentation] Nucleic acid-sensing Toll-like receptors: their recognition and regulation (2013)
  • Author(s): Kensuke Miyake
  • Organizer: The 21th international symposium of macrophage molecular and cellular biology
  • Place of Presentation: Tokyo
  • Invited
• [Presentation] TLR logistics by Unc93B1 as a mechanism regulating autoimmunity (2013)
  • Author(s): Kensuke Miyake
  • Organizer: American Association of Immunologists (AAI) annual meeting 2013
  • Place of Presentation: Hawaii, USA
  • Invited
• [Presentation] Toll-like receptor logistics as a mechanism regulating autoimmunity (2013)
  • Author(s): Kensuke Miyake
  • Organizer: The 5th East Asian Group of Rheumatology
  • Place of Presentation: Seoul, South Korea
  • Invited
• [Presentation] TLR logistics by Unc93B1 as a mechanism regulating autoimmunity (2013)
  • Author(s): Kensuke Miyake
  • Organizer: Frontiers in Innate Immunity
  • Place of Presentation: Strasbourg, France
  • Invited
• [Presentation] Nucleic acid-sensing Toll-like receptors: their recognition and regulation (2013)
  • Author(s): Kensuke Miyake
  • Organizer: The 86th annual meeting of the Japanese Society of Biochemical Society
  • Place of Presentation: Yokohama Japan
  • Invited
• [Presentation] Toll-like receptor logistics by Unc93B1 (2012)
  • Organizer: Symposium"Homeostatic Inflammation against self-derived products" at The 85th Annual meeting of the Japanese Biochemical Society
  • Place of Presentation: Fukuoka
  • Year and Date: 2012-12-15
• [Presentation] Toll-like receptor logistics by Unc93B1 (2012)
  • Author(s): Miyake K
  • Organizer: The 85th Annual meeting of the Japanese Biochemical Society
  • Place of Presentation: Fukuoka, Japan
  • Year and Date: 2012-12-15
  • Invited
• [Presentation] Toll-like receptor logistics by Unc93B1 (2012)
  • Organizer: Symposium in The biennial meeting of International endotoxin and innate immunity society
  • Place of Presentation: Tokyo
  • Year and Date: 2012-10-24
• [Presentation] Toll-like receptor logistics by Unc93B1 (2012)
  • Author(s): Miyake K
  • Organizer: The biennial meeting of International endotoxin and innate immunity society
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2012-10-24
  • Invited
• [Presentation] Toll-like receptor logistics by Unc93B1 as a mechanism regulating autoimmunity (2012)
  • Organizer: French-Japanese Meeting "Immune defenses in humans and model organisms
  • Place of Presentation: Embassy of France in Japan
  • Year and Date: 2012-09-21
• [Presentation] Toll-like receptor logistics by Unc93B1 as a mechanism regulating autoimmunity (2012)
  • Author(s): Miyake K
  • Organizer: French-Japanese Meeting “Immune defenses in humans and model organisms.
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2012-09-21
  • Invited
• [Presentation] Toll-like receptor 7 in plasmacytoid DCs as a target for enhancing anti-tumor immunity (2012)
  • Organizer: The 71st Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Sapporo
  • Year and Date: 2012-09-20
• [Presentation] Toll-like receptor 7 in plasmacytoid DCs as a target for enhancing anti-tumor immunity (2012)
  • Author(s): Miyake K
  • Organizer: The 71st Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Sapporo, Japan
  • Year and Date: 2012-09-20
  • Invited
• [Presentation] Toll-like receptor logistics by Unc93B1 (2012)
  • Organizer: The 11th Awaji international forum on infection and immunity
  • Place of Presentation: Awaji
  • Year and Date: 2012-09-12
• [Presentation] Toll-like receptor logistics by Unc93B1 (2012)
  • Author(s): Miyake K
  • Organizer: The 11th Awaji international forum on infection and immunity
  • Place of Presentation: Awaji, Japan
  • Year and Date: 2012-09-12
  • Invited
• [Presentation] Toll-like receptor logistics by Unc93B1 (2012)
  • Author(s): Miyake K
  • Organizer: Novo Nordisk Innovation summit on chronic inflammation and autoimmune diseases
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2012-04-18
  • Invited
• [Presentation] Human TLR4 polymorphisms influence cell surface expression and responses of TLR4 (2011)
  • Author(s): Natsuko Yamakawa, Sachiko Akashi-Takamura, Umeharu Ohto, Natsuko Tanimura, Toshiyuki Shimizu, Kensuke Miyake
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉県)
  • Year and Date: 2011-11-28
• [Presentation] Unc93 homolog B1 restricts lethal homeostatic inflammation by controlling TLR7 and TLR9 responses (2011)
  • Author(s): Ryutaro Fukui, Kensuke Miyake
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉県)(招待講演)
  • Year and Date: 2011-11-27
• [Presentation] MD-1 regulates the production of anti-phospholipid antibody (2011)
  • Author(s): Sachiko Akashi-Takamura, Natsuko Yamakawa, Kensuke Miyake
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ(千葉県)
  • Year and Date: 2011-11-27
• [Presentation] Roles for Unc93 homolog B1-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 regulates the balance of toll-like receptor 7 and to 11-like receptor9 responses reciprocally in dendritic cells (2009)
  • Author(s): Fukui, et al.
  • Organizer: Tri-Society Annual Conference
  • Place of Presentation: リスボン、ポルトガル
  • Year and Date: 2009-10-20
• [Presentation] Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells towards DNA-but against RNA-sensing. (2009)
  • Author(s): 三宅健介
  • Organizer: Cold Spring Harbor meeting
  • Place of Presentation: 米国Cold Spring Harbor
• [Presentation] Toll-like receptor logistics as a mechanism regulating autoimmunity
  • Organizer: The 5th East Asian Group of Rheumatology
  • Place of Presentation: Seoul, South Korea
• [Presentation] TLR logistics by Unc93B1 as a mechanism regulating autoimmunity
  • Organizer: France-Japan joint forum, Frontiers in Innate Immunity
  • Place of Presentation: Univ. Strasbourg, Strasbourg, France
• [Presentation] Nucleic acid-sensing Toll-like receptors : their recognition and regulation
  • Organizer: The 86th annual meeting of the Japanese Society of Biochemical Society
  • Place of Presentation: Yokohama, Japan
• [Presentation] Mechanisms Regulating Nucleic Acid Sensing Toll-like Receptors
  • Organizer: The 58th annual meeting of Japanese College of Rheumatology
  • Place of Presentation: International symposium, Tokyo, Japan
• [Remarks]
  • URL: http://www.shizen-enshow.jp/
• [Patent(Industrial Property Rights)] 炎症性疾患の予防又は治療剤 (2013)
  • Inventor(s): 三宅健介、菅野敦夫、恩地正浩、本井祐二
  • Industrial Property Rights Holder: 東京大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-089575
  • Filing Date: 2013-04-22