Molecular basis underlying Toll-like receptor logistics

• Project/Area Number: 25253032
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Immunology
• 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(Renkei-kenkyūsha): SAITOH Shin-Ichiroh 東京大学, 医科学研究所, 助教 (90361625)
• Project Period (FY): 2013-10-21 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥43,940,000 (Direct Cost: ¥33,800,000、Indirect Cost: ¥10,140,000); Fiscal Year 2015: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000); Fiscal Year 2014: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000); Fiscal Year 2013: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000)
• Keywords: 自然免疫 / Toll様受容体

Outline of Final Research Achievements

Toll-like receptors (TLRs) sense microbial products and induce defense responses. TLRs also respond to self derived products and causes inflammatory diseases. The present study focused on the molecular mechanism regulating TLR responses. TLR trafficking in endolysosomes controls TLR responses. The roles of small GTPases in TLR trafficking was studied. We also studied the roles of: proteolytic processing of the extracellular domain of TLR9 and TLR3 in their responses; and DNase II in DNA processing for TLR9 responses.These results show that TLR responses are regulated at a variety of processes.

Research Products

• [Journal Article] Type I IFN Contributes to the Phenotype of Unc93b1D34A/D34A Mice by Regulating TLR7 Expression in B Cells and Dendritic Cells (2016)
  • Author(s): Fukui R, Kanno A, Miyake K
  • Journal Title: J Immunol Volume: 196 Issue: 1 Pages: 416-427
  • DOI: 10.4049/jimmunol.1500071
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Toll-like receptor 8 senses degradation products of single-stranded RNA. (2015)
  • Author(s): Tanji H, Ohto U, Shibata T, Taoka M, Yamauchi Y, Isobe T, Miyake K,
  • Journal Title: Nat Struct Mol Biol. Volume: 22 Issue: 2 Pages: 109-115
  • DOI: 10.1038/nsmb.2943
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cell-intrinsic expression of TLR9 in autoreactive B cells constrains BCR/TLR7-dependent responses. (2015)
  • Author(s): Nundel K, Green NM, Shaffer AL, Moody KL, Busto P, Eilat D, Miyake K, Oropallo MA, Cancro MP, Marshak-Rothstein A
  • Journal Title: J Immunol. Volume: 194 Issue: 6 Pages: 2504-2512
  • DOI: 10.4049/jimmunol.1402425
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 9. (2015)
  • Author(s): Ohto, U., Shibata, T., Tanji, H., Krayukhina, E., Uchiyama, S., Miyake, K., and Shimizu, T.
  • Journal Title: Nature Volume: 520 Issue: 7549 Pages: 702-705
  • DOI: 10.1038/nature14138
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] DNase II-dependent DNA digestion is required for DNA sensing by TLR9 (2015)
  • Author(s): Chan MP, Onji M, Fukui R, Kawane K, Shibata T, Saitoh SI, Ohto U, Shimizu T, Barber GN, *Miyake K
  • Journal Title: Nat Commun Volume: 6 Issue: 1 Pages: 5853-5853
  • DOI: 10.1038/ncomms6853
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Targeting cell surface TLR7 for therapeutic intervention in autoimmune diseases (2015)
  • Author(s): Kanno A, Tanimura N, Ishizaki M, Ohko K, Motoi Y, Onji M, Fukui R, Shimozato T, Yamamoto K, Shibata T, Sano S, Sugahara-Tobinai A, Takai T, Ohto U, Shimizu T, Saitoh S, Miyake K.
  • Journal Title: Nature Communications Volume: 6 Issue: 1 Pages: 6119-6119
  • DOI: 10.1038/ncomms7119
  • Peer Reviewed / Open Access
• [Journal Article] Mucolipin 1 positively regulates TLR7 responses in dendritic cells by facilitating RNA transportation to lysosomes (2015)
  • Author(s): Li X, Saitoh S, Shibata T, Tanimura N, Fukui R, Miyake K.
  • Journal Title: International immunology Volume: 27 Issue: 2 Pages: 83-94
  • DOI: 10.1093/intimm/dxu086
  • Peer Reviewed / Open Access
• [Journal Article] Lipopeptides are signaled by Toll-like receptor 1, 2, and 6 in endolysosomes (2014)
  • Author(s): Motoi Y, Shibata T, Takahashi K, Kanno A, Murakami Y, Xiaobing L, Kasahara T, *Miyake K
  • Journal Title: Int Immunol Volume: 26 Issue: 10 Pages: 563-573
  • DOI: 10.1093/intimm/dxu054
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Roles of the Cleaved N-Terminal TLR3 Fragment and Cell Surface TLR3 in Double-Stranded RNA Sensing (2014)
  • Author(s): Murakami Y, Fukui R, Motoi Y, Kanno A, Shibata T, Tanimura N, Saitoh SI, *Miyake K
  • Journal Title: J Immunol Volume: 193 Pages: 5208-5217
  • Peer Reviewed / Acknowledgement Compliant
• [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] 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
• [Presentation] Toll様受容体によるRNA認識におけるRNAプロセシングの役割 (2015)
  • Author(s): 三宅健介
  • Organizer: 第88回日本生化学会年会
  • Place of Presentation: 神戸ポートアイランド (兵庫県 神戸市）
  • Year and Date: 2015-12-01
  • Int'l Joint Research / Invited
• [Presentation] Innate Immune Response to nucleic acids in inflammatory disorders (2015)
  • Author(s): Kensuke Miyake
  • Organizer: the 63rd annual meeting of the Japanese Association of Dental Research
  • Place of Presentation: 福岡国際会議場（福岡県 福岡市）
  • Year and Date: 2015-10-30
  • Int'l Joint Research / Invited
• [Presentation] The role of Nucleic acid processing in nucleic acid sensing by Toll-like receptors (2015)
  • Author(s): Kensuke Miyake
  • Organizer: Toll 2015
  • Place of Presentation: Marbella, Spain
  • Year and Date: 2015-09-30
  • Int'l Joint Research / Invited
• [Presentation] Nucleic Acid recognition by Toll-like receptors (2015)
  • Author(s): Kensuke Miyake
  • Organizer: National Institute of Chemistry meeting in slovenia
  • Place of Presentation: Ljubjana, Slovenia
  • Year and Date: 2015-06-24
  • Invited
• [Presentation] Nucleic acid recognition by Toll-like receptors (2015)
  • Author(s): Kensuke Miyake
  • Organizer: Innate Immunity Day, University of Massachusetts
  • Place of Presentation: Worcester, USA
  • Year and Date: 2015-05-20
  • Invited
• [Presentation] Toll様受容体の活性制御機構とその破綻 (2014)
  • Author(s): 三宅健介
  • Organizer: 第9回臨床ストレス応答学会
  • Place of Presentation: 岡山大学鹿田キャンパス
  • Year and Date: 2014-11-01 – 2014-11-02
  • Invited
• [Presentation] Mechanisms regulating nucleic acid sensing Toll-like receptors (2014)
  • Author(s): 三宅健介
  • Organizer: 第13回国際エンドトキシン自然免疫学会
  • Place of Presentation: ソルトレークシティー 米国
  • Year and Date: 2014-10-23 – 2014-10-25
  • Invited
• [Presentation] Toll様受容体による核酸認識の制御機構 (2014)
  • Author(s): 三宅健介
  • Organizer: 日本生化学会
  • Place of Presentation: 京都国際会館
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] Toll様受容体の活性制御機構とその破綻 (2014)
  • Author(s): 三宅健介
  • Organizer: 日本乾癬学会
  • Place of Presentation: 高知市文化プラザ カルポート
  • Year and Date: 2014-09-19 – 2014-09-20
  • Invited
• [Presentation] Mechanisms regulating Nucleic acid-sensing Toll-like receptors (2014)
  • Author(s): 三宅健介
  • Organizer: 日本リウマチ学会
  • Place of Presentation: 新高輪プリンスホテル
  • Year and Date: 2014-04-24 – 2014-04-25
  • Invited