title: RIG-I and MDA-5 detection of viral RNA-dependent RNA polymerase activity restricts positive-strand RNA virus replication.
abstract: Type I interferons (IFN) are important for antiviral responses. Melanoma differentiation-associated gene 5 (MDA-5) and retinoic acid-induced gene I (RIG-I) proteins detect cytosolic double-stranded RNA (dsRNA) or 5'-triphosphate (5'-ppp) RNA and mediate IFN production. Cytosolic 5'-ppp RNA and dsRNA are generated during viral RNA replication and transcription by viral RNA replicases [RNA-dependent RNA polymerases (RdRp)]. Here, we show that the Semliki Forest virus (SFV) RNA replicase can induce IFN-β independently of viral RNA replication and transcription. The SFV replicase converts host cell RNA into 5'-ppp dsRNA and induces IFN-β through the RIG-I and MDA-5 pathways. Inactivation of the SFV replicase RdRp activity prevents IFN-β induction. These IFN-inducing modified host cell RNAs are abundantly produced during both wild-type SFV and its non-pathogenic mutant infection. Furthermore, in contrast to the wild-type SFV replicase a non-pathogenic mutant replicase triggers increased IFN-β production, which leads to a shutdown of virus replication. These results suggest that host cells can restrict RNA virus replication by detecting the products of unspecific viral replicase RdRp activity.
authors.affiliation: Department of Biomedical Technology, Institute of Technology, University of Tartu, Tartu, Estonia.
authors.forename: Andrei
authors.initials: A
authors.lastname: Nikonov
authors.forename: Tarmo
authors.initials: T
authors.lastname: Mölder
authors.forename: Rein
authors.initials: R
authors.lastname: Sikut
authors.forename: Kaja
authors.initials: K
authors.lastname: Kiiver
authors.forename: Andres
authors.initials: A
authors.lastname: Männik
authors.forename: Urve
authors.initials: U
authors.lastname: Toots
authors.forename: Aleksei
authors.initials: A
authors.lastname: Lulla
authors.forename: Valeria
authors.initials: V
authors.lastname: Lulla
authors.forename: Age
authors.initials: A
authors.lastname: Utt
authors.forename: Andres
authors.initials: A
authors.lastname: Merits
authors.forename: Mart
authors.initials: M
authors.lastname: Ustav
mesh_terms: D018354:Alphavirus Infections / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000072640:Interferon-Induced Helicase, IFIH1; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism; D051379:Mice; D012330:RNA, Double-Stranded / Q000096:biosynthesis* / Q000235:genetics; D012367:RNA, Viral / Q000096:biosynthesis* / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic; D012672:Semliki forest virus / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D012330:RNA, Double-Stranded; D012367:RNA, Viral; D011971:Receptors, Immunologic; D014764:Viral Proteins; D016899:Interferon-beta; D012324:RNA-Dependent RNA Polymerase; C452820:RIGI protein, human; C503356:Ddx58 protein, mouse; C452815:IFIH1 protein, human; C510592:Ifih1 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1
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