title: Apoptosis induced by mammalian reovirus is beta interferon (IFN) independent and enhanced by IFN regulatory factor 3- and NF-κB-dependent expression of Noxa.
abstract: A variety of signal transduction pathways are activated in response to viral infection, which dampen viral replication and transmission. These mechanisms involve both the induction of type I interferons (IFNs), which evoke an antiviral state, and the triggering of apoptosis. Mammalian orthoreoviruses are double-stranded RNA viruses that elicit apoptosis in vitro and in vivo. The transcription factors interferon regulatory factor 3 (IRF-3) and nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) are required for the expression of IFN-β and the efficient induction of apoptosis in reovirus-infected cells. However, it is not known whether IFN-β induction is required for apoptosis, nor have the genes induced by IRF-3 and NF-κB that are responsible for apoptosis been identified. To determine whether IFN-β is required for reovirus-induced apoptosis, we used type I IFN receptor-deficient cells, IFN-specific antibodies, and recombinant IFN-β. We found that IFN synthesis and signaling are dispensable for the apoptosis of reovirus-infected cells. These results indicate that the apoptotic response following reovirus infection is mediated directly by genes responsive to IRF-3 and NF-κB. Noxa is a proapoptotic BH3-domain-only protein of the Bcl-2 family that requires IRF-3 and NF-κB for efficient expression. We found that Noxa is strongly induced at late times (36 to 48 h) following reovirus infection in a manner dependent on IRF-3 and NF-κB. The level of apoptosis induced by reovirus is significantly diminished in cells lacking Noxa, indicating a key prodeath function for this molecule during reovirus infection. These results suggest that prolonged innate immune response signaling induces apoptosis by eliciting Noxa expression in reovirus-infected cells.
authors.affiliation: Department of Biology, Colgate University, Hamilton, New York, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Knowlton
authors.forename: Terence S
authors.initials: TS
authors.lastname: Dermody
authors.forename: Geoffrey H
authors.initials: GH
authors.lastname: Holm
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D016899:Interferon-beta / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D012087:Reoviridae / Q000254:growth & development / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D017931:DNA Primers; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D016328:NF-kappa B; C408009:Pmaip1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016899:Interferon-beta
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