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

Nature Communications 2013 Jun 11;4:1949. doi: 10.1038/ncomms2949
Masahiro Onji1,2, Atsuo Kanno1, Shin-Ichiroh Saitoh1, Ryutaro Fukui1, Yuji Motoi1, Takuma Shibata1,3, Fumi Matsumoto1, Aayam Lamichhane4, Shintaro Sato4, Hiroshi Kiyono4, Kazuhide Yamamoto2 & Kensuke Miyake1,3
1 Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108 8639, Japan. 2 Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700 8558, Japan. 3 Laboratory of Innate Immunity, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108 8639, Japan. 4 Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minatoku, Tokyo 108 8639, Japan.

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 TLR9NþC. 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 TLR9NþC complex is a bona fide DNA sensor.