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

Masahiro Onji, Atsuo Kanno, Shin-Ichiroh Saitoh, Ryutaro Fukui, Yuji Motoi, Takuma Shibata, Fumi Matsumoto, Aayam Lamichhane, Shintaro Sato, Hiroshi Kiyono, Kazuhide Yamamoto and Kensuke Miyake ()
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Masahiro Onji: The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai
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
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

Nature Communications, 2013, vol. 4, issue 1, 1-10

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2949

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