title: 2'-O methylation of the viral mRNA cap evades host restriction by IFIT family members.
abstract: Cellular messenger RNA (mRNA) of higher eukaryotes and many viral RNAs are methylated at the N-7 and 2'-O positions of the 5' guanosine cap by specific nuclear and cytoplasmic methyltransferases (MTases), respectively. Whereas N-7 methylation is essential for RNA translation and stability, the function of 2'-O methylation has remained uncertain since its discovery 35 years ago. Here we show that a West Nile virus (WNV) mutant (E218A) that lacks 2'-O MTase activity was attenuated in wild-type primary cells and mice but was pathogenic in the absence of type I interferon (IFN) signalling. 2'-O methylation of viral RNA did not affect IFN induction in WNV-infected fibroblasts but instead modulated the antiviral effects of IFN-induced proteins with tetratricopeptide repeats (IFIT), which are interferon-stimulated genes (ISGs) implicated in regulation of protein translation. Poxvirus and coronavirus mutants that lacked 2'-O MTase activity similarly showed enhanced sensitivity to the antiviral actions of IFN and, specifically, IFIT proteins. Our results demonstrate that the 2'-O methylation of the 5' cap of viral RNA functions to subvert innate host antiviral responses through escape of IFIT-mediated suppression, and suggest an evolutionary explanation for 2'-O methylation of cellular mRNA: to distinguish self from non-self RNA. Differential methylation of cytoplasmic RNA probably serves as an example for pattern recognition and restriction of propagation of foreign viral RNA in host cells.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Stephane
authors.initials: S
authors.lastname: Daffis
authors.forename: Kristy J
authors.initials: KJ
authors.lastname: Szretter
authors.forename: Jill
authors.initials: J
authors.lastname: Schriewer
authors.forename: Jianqing
authors.initials: J
authors.lastname: Li
authors.forename: Soonjeon
authors.initials: S
authors.lastname: Youn
authors.forename: John
authors.initials: J
authors.lastname: Errett
authors.forename: Tsai-Yu
authors.initials: TY
authors.lastname: Lin
authors.forename: Stewart
authors.initials: S
authors.lastname: Schneller
authors.forename: Roland
authors.initials: R
authors.lastname: Zust
authors.forename: Hongping
authors.initials: H
authors.lastname: Dong
authors.forename: Volker
authors.initials: V
authors.lastname: Thiel
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
authors.forename: Volker
authors.initials: V
authors.lastname: Fensterl
authors.forename: William B
authors.initials: WB
authors.lastname: Klimstra
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Pierson
authors.forename: R Mark
authors.initials: RM
authors.lastname: Buller
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017934:Coronavirus / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000502:physiology; D005347:Fibroblasts; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D007372:Interferons / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D018448:Models, Immunological; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011212:Poxviridae / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000502:physiology; D014176:Protein Biosynthesis / Q000276:immunology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012315:RNA Caps / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012367:RNA, Viral / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016601:RNA-Binding Proteins; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D015996:Survival Rate; D014779:Virus Replication; D014902:West Nile virus / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C110985:IFIT5 protein, human; C092573:Ifit1 protein, mouse; C092572:Ifit2 protein, mouse; C508032:Ifnar1 protein, mouse; D009363:Neoplasm Proteins; D011506:Proteins; D012315:RNA Caps; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D053633:Receptor, Interferon alpha-beta; D007372:Interferons; D008780:Methyltransferases