title: Poxvirus decapping enzymes enhance virulence by preventing the accumulation of dsRNA and the induction of innate antiviral responses.
abstract: Poxvirus replication involves synthesis of double-stranded RNA (dsRNA), which can trigger antiviral responses by inducing phosphorylation-mediated activation of protein kinase R (PKR) and stimulating 2'5'-oligoadenylate synthetase (OAS). PKR inactivates the translation initiation factor eIF2α via phosphorylation, while OAS induces the endonuclease RNase L to degrade RNA. We show that poxvirus decapping enzymes D9 and D10, which remove caps from mRNAs, inhibit these antiviral responses by preventing dsRNA accumulation. Catalytic site mutations of D9 and D10, but not of either enzyme alone, halt vaccinia virus late protein synthesis and inhibit virus replication. Infection with the D9-D10 mutant was accompanied by massive mRNA reduction, cleavage of ribosomal RNA, and phosphorylation of PKR and eIF2α that correlated with a ∼ 15-fold increase in dsRNA compared to wild-type virus. Additionally, mouse studies show extreme attenuation of the mutant virus. Thus, vaccinia virus decapping, in addition to targeting mRNAs for degradation, prevents dsRNA accumulation and anti-viral responses.
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-3210, USA.
authors.forename: Shin-Wu
authors.initials: SW
authors.lastname: Liu
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-3210, USA.
authors.forename: George C
authors.initials: GC
authors.lastname: Katsafanas
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-3210, USA.
authors.forename: Ruikang
authors.initials: R
authors.lastname: Liu
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-3210, USA.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wyatt
authors.affiliation: Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-3210, USA. Electronic address: bmoss@nih.gov.
authors.forename: Bernard
authors.initials: B
authors.lastname: Moss
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004722:Endoribonucleases / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D012330:RNA, Double-Stranded / Q000378:metabolism*; D014616:Vaccinia virus / Q000201:enzymology* / Q000254:growth & development / Q000276:immunology* / Q000502:physiology; D014764:Viral Proteins / Q000378:metabolism; D014774:Virulence; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D015852:Eukaryotic Initiation Factor-2; D012330:RNA, Double-Stranded; D014764:Viral Proteins; C030052:mRNA decapping enzymes; D019892:eIF-2 Kinase; D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases