title: Toll-like receptor 3 recognizes incomplete stem structures in single-stranded viral RNA.
abstract: Endosomal Toll-like receptor 3 (TLR3) serves as a sensor of viral infection and sterile tissue necrosis. Although TLR3 recognizes double-stranded RNA, little is known about structural features of virus- or host-derived RNAs that activate TLR3 in infection/inflammatory states. Here we demonstrate that poliovirus-derived single-stranded RNA segments harbouring stem structures with bulge/internal loops are potent TLR3 agonists. Functional poliovirus-RNAs are resistant to degradation and efficiently induce interferon-α/β and proinflammatory cytokines in human and mouse cells in a TLR3-dependent manner. The N- and C-terminal double-stranded RNA-binding sites of TLR3 are required for poliovirus-RNA-mediated TLR3 activation. Like polyriboinosinic:polyribocytidylic acid, a synthetic double-stranded RNA, these RNAs are internalized into cells via raftlin-mediated endocytosis and colocalized with TLR3. Raftlin-associated RNA uptake machinery and the TLR3 RNA-sensing system appear to recognize an appropriate topology of multiple RNA duplexes in poliovirus-RNAs. Hence, TLR3 is a sensor of extracellular viral/host RNA with stable stem structures derived from infection or inflammation-damaged cells.
authors.affiliation: Department of Microbiology and Immunology, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060-8638, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Tatematsu
authors.forename: Fumiko
authors.initials: F
authors.lastname: Nishikawa
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D001665:Binding Sites; D039521:CD11c Antigen / Q000378:metabolism; D002474:Cell-Free System; D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D004705:Endocytosis; D004722:Endoribonucleases / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis; D016899:Interferon-beta / Q000096:biosynthesis; D051379:Mice; D009690:Nucleic Acid Conformation; D017955:Poliovirus / Q000378:metabolism*; D020871:RNA Stability; D012330:RNA, Double-Stranded / Q000378:metabolism; D012367:RNA, Viral / Q000737:chemistry* / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D039521:CD11c Antigen; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D007370:Interferon Type I; C422955:MazF protein, E coli; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D051196:Toll-Like Receptor 3; D016899:Interferon-beta; D004722:Endoribonucleases