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2'-O methylation of the viral mRNA cap evades host restriction by IFIT family members

机译：病毒mRNA帽的2'-O甲基化避免了IFIT家族成员对宿主的限制

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摘要

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 methyltrans-ferases (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 tetra-tricopeptide 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.
机译：高等真核生物的细胞信使RNA（mRNA）和许多病毒RNA在5'鸟苷帽的N-7和2'-O位置分别被特定的核和胞质甲基转移酶（MTase）甲基化。尽管N-7甲基化对于RNA翻译和稳定性至关重要，但自35年前发现以来，2'-O甲基化的功能仍然不确定。在这里，我们显示了缺乏2'-O MTase活性的西尼罗河病毒（WNV）突变体（E218A）在野生型原代细胞和小鼠中减毒，但在没有I型干扰素（IFN）信号传导的情况下具有致病性。病毒RNA的2'-O甲基化作用不会影响WNV感染的成纤维细胞中的IFN诱导，而是通过四三肽重复序列（IFIT）调节了IFN诱导的蛋白的抗病毒作用，四重复肽重复序列是干扰素刺激的基因（ISG），参与调控蛋白质翻译。缺乏2'-O MTase活性的痘病毒和冠状病毒突变体同样显示出对IFN尤其是IFIT蛋白抗病毒作用的敏感性增强。我们的结果表明，病毒RNA 5'帽的2'-O甲基化功能通过逃避IFIT介导的抑制作用来破坏先天的宿主抗病毒反应，并提出了细胞mRNA 2'-O甲基化的进化解释：来自非自身RNA的自身。胞质RNA的甲基化差异可能是模式识别和限制外源病毒RNA在宿主细胞中繁殖的一个例子。

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  • 来源
    《Nature》 |2010年第7322期|p.452-456|共5页
  • 作者

    Stephane Daffis; Kristy J. Szretter; Jill Schriewer; Jianqing Li; Soonjeon Youn; John Errett; Tsai-Yu Lin; Stewart Schneller; Roland Zust; Hongping Dong; Volker Thiel; Ganes C. Sen; Volker Fensterl; William B. Klimstra; Theodore C. Pierson; R. Mark Buller; Michael Gale Jr; Pei-Yong Shi; Michael S. Diamond;

  • 作者单位

    Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA;

    rnDepartment of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA;

    rnDepartment of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St Louis, Missouri 63104, USA;

    rnDepartment of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA;

    rnDepartment of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA;

    rnDepartment of Immunology, University of Washington School of Medicine, Seattle, Washington 98195-7650, USA;

    rnViral Pathogenesis Section, Laboratory of Viral Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Department of Chemistry and Biochemistry, Auburn University, Auburn, Alabama 36849-5312, USA;

    rnInstitute of Immunobiology, Kantonal Hospital St Gallen, 9007 St Gallen, Switzerland;

    rnWadsworth Center, New York State Department of Health, Albany, New York 12208, USA;

    rnInstitute of Immunobiology, Kantonal Hospital St Gallen, 9007 St Gallen, Switzerland Vetsuisse Faculty, University of Zuerich, 8006 Zurich, Switzerland;

    rnCleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA;

    rnCleveland Clinic, Lerner Research Institute, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA;

    rnDepartment of Microbiology and Molecular Genetics, University of Pittsburgh Medical School, 3501 Fifth Avenue, Pittsburgh, Pennsylvania 15261, USA;

    rnViral Pathogenesis Section, Laboratory of Viral Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA;

    Midwest, Pacific Northwest, and Northeast Regional Centers for Biodefense and Emerginglnfectious Diseases Research Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St Louis, Missouri 63104, USA;

    rnMidwest, Pacific Northwest, and Northeast Regional Centers for Biodefense and Emerginglnfectious Diseases Research Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98195-7650, USA;

    rnMidwest, Pacific Northwest, and Northeast Regional Centers for Biodefense and Emerginglnfectious Diseases Research Wadsworth Center, New York State Department of Health, Albany, New York 12208, USA;

    rnDepartment of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA Departmentof Pathology & Immunology, Washington University School of Medici ne.St Louis, Missouri 63110, USA Midwest, Pacific Northwest, and Northeast Regional Centers for Biodefense and Emerginglnfectious Diseases Research;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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