title: An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing.
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.
authors.affiliation: 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.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Onji
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kanno
authors.forename: Shin-Ichiroh
authors.initials: S
authors.lastname: Saitoh
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Fukui
authors.forename: Yuji
authors.initials: Y
authors.lastname: Motoi
authors.forename: Takuma
authors.initials: T
authors.lastname: Shibata
authors.forename: Fumi
authors.initials: F
authors.lastname: Matsumoto
authors.forename: Aayam
authors.initials: A
authors.lastname: Lamichhane
authors.forename: Shintaro
authors.initials: S
authors.lastname: Sato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyono
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Kensuke
authors.initials: K
authors.lastname: Miyake
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology; D002462:Cell Membrane / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004247:DNA / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism; D006801:Humans; D000090263:Leucine-Rich Repeat Proteins; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013329:Structure-Activity Relationship; D051217:Toll-Like Receptor 9 / Q000737:chemistry* / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; D000090263:Leucine-Rich Repeat Proteins; D011506:Proteins; D051217:Toll-Like Receptor 9; D004247:DNA