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An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing

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  • Masahiro Onji

    (The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai
    Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho)

  • Atsuo Kanno

    (The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai)

  • Shin-Ichiroh Saitoh

    (The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai)

  • Ryutaro Fukui

    (The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai)

  • Yuji Motoi

    (The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai)

  • Takuma Shibata

    (The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai
    Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai)

  • Fumi Matsumoto

    (The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai)

  • Aayam Lamichhane

    (The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai)

  • Shintaro Sato

    (The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai)

  • Hiroshi Kiyono

    (The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai)

  • Kazuhide Yamamoto

    (Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho)

  • Kensuke Miyake

    (The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai
    Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai)

Abstract

Toll-like receptor 9 (TLR9) is an innate immune sensor for microbial DNA that erroneously responds to self DNA in autoimmune disease. To prevent autoimmune responses, Toll-like receptor 9 is excluded from the cell surface and silenced until the N-terminal half of the ectodomain (TLR9N) is cleaved off in the endolysosome. Truncated Toll-like receptor 9 (TLR9C) senses ingested microbial DNA, although the precise role of the truncation remains controversial. Here we show that TLR9 is expressed on the surface of splenic dendritic cells. Following the cleavage of TLR9 in the endolysosome, N-terminal half of the ectodomain remains associated with truncated TLR9, forming the complex TLR9N+C. The TLR9-dependent cytokine production by Tlr9−/− dendritic cells is rescued by a combination of TLR9N and TLR9C, but not by TLR9C alone. These results demonstrate that the TLR9N+C complex is a bona fide DNA sensor.

Suggested Citation

  • Masahiro Onji & Atsuo Kanno & Shin-Ichiroh Saitoh & Ryutaro Fukui & Yuji Motoi & Takuma Shibata & Fumi Matsumoto & Aayam Lamichhane & Shintaro Sato & Hiroshi Kiyono & Kazuhide Yamamoto & Kensuke Miyak, 2013. "An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing," Nature Communications, Nature, vol. 4(1), pages 1-10, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2949
    DOI: 10.1038/ncomms2949
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