title: Involvement of the interferon-regulated antiviral proteins PKR and RNase L in reovirus-induced shutoff of cellular translation.
abstract: Cellular translation is inhibited following infection with most strains of reovirus, but the mechanisms responsible for this phenomenon remain to be elucidated. The extent of host shutoff varies in a strain-dependent manner; infection with the majority of strains leads to strong host shutoff, while infection with strain Dearing results in minimal inhibition of cellular translation. A genetic study with reassortant viruses and subsequent biochemical analyses led to the hypothesis that the interferon-induced, double-stranded RNA-activated protein kinase, PKR, is responsible for reovirus-induced host shutoff. To directly determine whether PKR is responsible for reovirus-induced host shutoff, we used a panel of reovirus strains and mouse embryo fibroblasts derived from knockout mice. This approach revealed that PKR contributes to but is not wholly responsible for reovirus-induced host shutoff. Studies with cells lacking RNase L, the endoribonuclease component of the interferon-regulated 2',5'-oligoadenylate synthetase-RNase L system, demonstrated that RNase L also down-regulates cellular protein synthesis in reovirus-infected cells. In many viral systems, PKR and RNase L have well-characterized antiviral functions. An analysis of reovirus replication in cells lacking these molecules indicated that, while they contributed to host shutoff, neither PKR nor RNase L exerted an antiviral effect on reovirus growth. In fact, some strains of reovirus replicated more efficiently in the presence of PKR and RNase L than in their absence. Data presented in this report illustrate that the inhibition of cellular translation following reovirus infection is complex and involves multiple interferon-regulated gene products. In addition, our results suggest that reovirus has evolved effective mechanisms to avoid the actions of the interferon-stimulated antiviral pathways that include PKR and RNase L and may even benefit from their expression.
authors.affiliation: Department of Microbiology, University of Minnesota, 420 Delaware St., Minneapolis, MN 55455, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Smith
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Schmechel
authors.forename: Bryan R G
authors.initials: BR
authors.lastname: Williams
authors.forename: Robert H
authors.initials: RH
authors.lastname: Silverman
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Schiff
mesh_terms: D000818:Animals; D002460:Cell Line; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D016898:Interferon-alpha / Q000494:pharmacology*; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012330:RNA, Double-Stranded / Q000235:genetics / Q000502:physiology; D012087:Reoviridae / Q000235:genetics / Q000502:physiology*; D014764:Viral Proteins / Q000032:analysis / Q000096:biosynthesis; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D016898:Interferon-alpha; D011500:Protein Synthesis Inhibitors; D012330:RNA, Double-Stranded; D014764:Viral Proteins; D019892:eIF-2 Kinase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease