title: Ribose 2'-O-methylation provides a molecular signature for the distinction of self and non-self mRNA dependent on the RNA sensor Mda5.
abstract: The 5' cap structures of higher eukaryote mRNAs have ribose 2'-O-methylation. Likewise, many viruses that replicate in the cytoplasm of eukaryotes have evolved 2'-O-methyltransferases to autonomously modify their mRNAs. However, a defined biological role for 2'-O-methylation of mRNA remains elusive. Here we show that 2'-O-methylation of viral mRNA was critically involved in subverting the induction of type I interferon. We demonstrate that human and mouse coronavirus mutants lacking 2'-O-methyltransferase activity induced higher expression of type I interferon and were highly sensitive to type I interferon. Notably, the induction of type I interferon by viruses deficient in 2'-O-methyltransferase was dependent on the cytoplasmic RNA sensor Mda5. This link between Mda5-mediated sensing of viral RNA and 2'-O-methylation of mRNA suggests that RNA modifications such as 2'-O-methylation provide a molecular signature for the discrimination of self and non-self mRNA.
authors.affiliation: Institute of Immunobiology, Kantonal Hospital St. Gallen, St. Gallen, Switzerland.
authors.forename: Roland
authors.initials: R
authors.lastname: Züst
authors.forename: Luisa
authors.initials: L
authors.lastname: Cervantes-Barragan
authors.forename: Matthias
authors.initials: M
authors.lastname: Habjan
authors.forename: Reinhard
authors.initials: R
authors.lastname: Maier
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Neuman
authors.forename: John
authors.initials: J
authors.lastname: Ziebuhr
authors.forename: Kristy J
authors.initials: KJ
authors.lastname: Szretter
authors.forename: Susan C
authors.initials: SC
authors.lastname: Baker
authors.forename: Winfried
authors.initials: W
authors.lastname: Barchet
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Siddell
authors.forename: Burkhard
authors.initials: B
authors.lastname: Ludewig
authors.forename: Volker
authors.initials: V
authors.lastname: Thiel
mesh_terms: D000818:Animals; D002460:Cell Line; D017934:Coronavirus / Q000472:pathogenicity / Q000502:physiology*; D018352:Coronavirus Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000072640:Interferon-Induced Helicase, IFIH1; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012367:RNA, Viral / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D051192:Receptors, Pattern Recognition / Q000235:genetics; D012266:Ribose / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014774:Virulence / Q000235:genetics; D014779:Virus Replication / Q000235:genetics
chemical_list: C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D012367:RNA, Viral; D051192:Receptors, Pattern Recognition; D014764:Viral Proteins; D053633:Receptor, Interferon alpha-beta; D012266:Ribose; D008780:Methyltransferases; C510592:Ifih1 protein, mouse; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1