Publication Date:
2010-11-19
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058805/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058805/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Daffis, Stephane -- Szretter, Kristy J -- Schriewer, Jill -- Li, Jianqing -- Youn, Soonjeon -- Errett, John -- Lin, Tsai-Yu -- Schneller, Stewart -- Zust, Roland -- Dong, Hongping -- Thiel, Volker -- Sen, Ganes C -- Fensterl, Volker -- Klimstra, William B -- Pierson, Theodore C -- Buller, R Mark -- Gale, Michael Jr -- Shi, Pei-Yong -- Diamond, Michael S -- R01 AI074973/AI/NIAID NIH HHS/ -- R01 AI56540/AI/NIAID NIH HHS/ -- R01 CA068782/CA/NCI NIH HHS/ -- R01 CA068782-24/CA/NCI NIH HHS/ -- U19 AI083019/AI/NIAID NIH HHS/ -- U54 AI057158/AI/NIAID NIH HHS/ -- U54 AI057160/AI/NIAID NIH HHS/ -- U54 AI057160-06/AI/NIAID NIH HHS/ -- U54 AI081680/AI/NIAID NIH HHS/ -- U54 AI081680-01/AI/NIAID NIH HHS/ -- England -- Nature. 2010 Nov 18;468(7322):452-6. doi: 10.1038/nature09489.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21085181" target="_blank"〉PubMed〈/a〉
Keywords:
3T3 Cells
;
Animals
;
Carrier Proteins/genetics/*metabolism
;
Cells, Cultured
;
Coronavirus/enzymology/genetics/immunology/physiology
;
Fibroblasts
;
Gene Expression Regulation/genetics/*immunology
;
Humans
;
Immunity, Innate/genetics/*immunology
;
Interferons/deficiency/genetics/*immunology
;
Methylation
;
Methyltransferases/metabolism
;
Mice
;
Mice, Inbred C57BL
;
Models, Genetic
;
Models, Immunological
;
Neoplasm Proteins/genetics/metabolism
;
Poxviridae/enzymology/genetics/immunology/physiology
;
Protein Biosynthesis/immunology
;
Proteins/genetics/*metabolism
;
RNA Caps/genetics/immunology/*metabolism
;
RNA, Viral/genetics/immunology/*metabolism
;
Receptor, Interferon alpha-beta/deficiency/genetics
;
Survival Rate
;
Virus Replication
;
West Nile virus/enzymology/genetics/immunology/physiology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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