Novel regulatory mechanism of TLR7/8 by ssRNA

• Project/Area Number: 26670235
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• 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): SHIBATA Takuma 東京大学, 医科学研究所, 助教 (30554505)
• Project Period (FY): 2014-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 自然免疫 / TLR7 / TLR8 / 一本鎖核酸 / Toll様受容体

Outline of Final Research Achievements

Toll-like receptor 7 (TLR7) and 8 were considered to recognize single-strand RNA (ssRNA). Although these receptors also respond to synthetic small chemical ligands, such as CL075 and R848, it remains to be determined whether these receptors sense natural small molecules or not. We find that TLR7 work as the sensor for guanosine (G) /2’-deoxyguanosine (dG) in the presence of ORN where ORN strengthens TLR7 interaction with G/dG. In addition, modified nucleosides such as 7-methylguanosine, 8-hydroxyguanosine and 8-hydroxydeoxyguanosine (8-OHdG), activated TLR7 with ORNs. Importantly, 8-OHdG -a well-known oxidative DNA damage marker with unknown function- induced strong cytokine production comparable to G and dG both in mouse and human immune cells. Our results shed light on the biological function of guanosine and modified guanosines in innate immune response.

Research Products

• [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] 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] 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
• [Presentation] Mechanisms regulating Nucleic acid-sensing Toll-like receptors (2015)
  • Author(s): 三宅健介
  • Organizer: 日本細菌学会
  • Place of Presentation: 岐阜県岐阜市
  • Year and Date: 2015-03-26
  • Invited
• [Presentation] 自然炎症における核酸代謝と核酸センサーの役割 (2015)
  • Author(s): 三宅健介
  • Organizer: 第8回IgG4関連疾患研究会
  • Place of Presentation: 福井カリーせんとホテル
  • Year and Date: 2015-03-21
  • Invited
• [Presentation] Human TLR7/TLR8 are sensors for nucleoside derivatives (2014)
  • Author(s): 柴田琢磨
  • Organizer: 日本免疫学会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2014-12-10 – 2014-12-12