title: A single naturally occurring 2'-O-methylation converts a TLR7- and TLR8-activating RNA into a TLR8-specific ligand.
abstract: TLR7 and TLR8 recognize RNA from pathogens and lead to subsequent immune stimulation. Here we demonstrate that a single naturally occurring 2'-O-methylation within a synthetic 18s rRNA derived RNA sequence prevents IFN-α production, however secretion of proinflammatory cytokines such as IL-6 is not impaired. By analysing TLR-deficient plasmacytoid dendritic cells and performing HEK293 genetic complementation assays we could demonstrate that the single 2'-O-methylation containing RNA still activated TLR8 but not TLR7. Therefore this specific 2'-O-ribose methylation in rRNA converts a TLR7/TLR8 ligand to an exclusively TLR8-specific ligand. Interestingly, other modifications at this position such as 2'-O-deoxy or 2'-fluoro had no strong modulating effect on TLR7 or TLR8 activation suggesting an important role of 2'-O-methylation for shaping differential TLR7 or TLR8 activation.
authors.affiliation: Institut für Immunologie, Philipps-Universität Marburg, BMFZ, Marburg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jung
authors.affiliation: Institut für Immunologie, Philipps-Universität Marburg, BMFZ, Marburg, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: von Thülen
authors.affiliation: Institut für Immunologie, Philipps-Universität Marburg, BMFZ, Marburg, Germany.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Laukemper
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, München, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Pigisch
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, München, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Hangel
authors.affiliation: Institut für Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universität München, München, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.affiliation: Institut für Immunologie, Philipps-Universität Marburg, BMFZ, Marburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kaufmann
authors.affiliation: Institut für Immunologie, Philipps-Universität Marburg, BMFZ, Marburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bauer
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis; D015850:Interleukin-6 / Q000378:metabolism; D008024:Ligands; D008745:Methylation; D051379:Mice; D012313:RNA / Q000737:chemistry* / Q000378:metabolism*; D012337:RNA, Ribosomal, 18S / Q000378:metabolism; D013379:Substrate Specificity; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000378:metabolism*
chemical_list: D016898:Interferon-alpha; D015850:Interleukin-6; D008024:Ligands; D012337:RNA, Ribosomal, 18S; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D012313:RNA