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

2013 Fiscal Year Final Research Report

• 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
• Keywords: Toll様受容体

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
  • DOI: 10.1073/pnas.1322838111
• [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.
  • DOI: 10.1093/intimm/dxt071
• [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 Pages: 1949
  • DOI: 10.1038/ncomms2949
• [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 Pages: 1426-1429
  • DOI: 10.1126/science.1229159
• [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] 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 Pages: 613-623
  • DOI: 10.1093/intimm/dxs068
• [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 Pages: 40611-40617
  • DOI: 10.1074/jbc.M112.404608
• [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 Pages: 7421-7426
  • DOI: 10.1073/pnas.1201193109
• [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 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
• [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
  • Year and Date: 20130520-21
• [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
  • Year and Date: 20130503-07
• [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)
  • 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 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 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 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] 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
  • Year and Date: 00000606-07
• [Presentation] Toll-like receptor logistics as a mechanism regulating autoimmunity
  • Organizer: The 5th East Asian Group of Rheumatology
  • Place of Presentation: Seoul, South Korea
  • Year and Date: 00000531-0601
• [Presentation] Nucleic acid-sensing Toll-like receptors : their recognition and regulation (0)
  • Organizer: The 86th annual meeting of the Japanese Society of Biochemical Society
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 00000913
• [Presentation] Mechanisms Regulating Nucleic Acid Sensing Toll-like Receptors (0)
  • Organizer: The 58th annual meeting of Japanese College of Rheumatology
  • Place of Presentation: International symposium, Tokyo, Japan
  • Year and Date: 00000424
• [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: 特願 2013-089575
  • Filing Date: 2013-04-22
  • Application Year: 2013