Retinoic Acid-inducible Gene-I and Interferon-β Promoter Stimulator-1 Augment Proapoptotic Responses Following Mammalian Reovirus Infection via Interferon Regulatory Factor-3

Abstract

During viral infection, cells initiate antiviral responses to contain replication and inhibit virus spread. One protective mechanism involves activation of transcription factors interferon regulatory factor-3 (IRF-3) and NF-B, resulting in secretion of the antiviral cytokine, interferon-␤. Another is induction of apoptosis, killing the host cell before virus disseminates. Mammalian reovirus induces both interferon-␤ and apoptosis, raising the possibility that both pathways are initiated by a common cellular sensor. We show here that reovirus activates IRF-3 with kinetics that parallel the activation of NF-B, a known mediator of reovirus-induced apoptosis. Activation of IRF-3 requires functional retinoic acid inducible gene-I and interferon-␤ promoter stimulator-1, but these intracellular sensors are dispensable for activation of NF-B. Interferon-␤ promoter stimulator-1 and IRF-3 are required for efficient apoptosis following reovirus infection, suggesting a common mechanism of antiviral cytokine induction and activation of the cell death response.A primary function of the innate immune system is to detect nascent viral infections and direct subsequent cellular responses. The innate immune system responds to infection by producing a range of soluble cytokines, such as interferon-␤ (IFN-␤), 5 that create an antiviral state in surrounding tissue. In response to these immune pressures, viruses have evolved multiple strategies for subverting innate immunity, which frequently center on manipulating cell death pathways. The interface between the innate immune response, viral infection, and the cellular apoptotic machinery is therefore a critical nexus of disease pathogenesis.Cells possess a variety of sensors to detect invading pathogens. Toll-like receptors (TLRs) and other pattern recognition receptors, including the nucleotide-binding oligomerization domain proteins and RNA helicases such as retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated protein-5 (Mda-5), recognize viral pathogen-associated molecular patterns (1). TLRs are expressed on the cell surface and recognize extracellular pathogen-associated molecular patterns, whereas RIG-I and Mda-5 detect intracellular viral RNA products (2-4). RIG-I recognizes viral RNAs from the Flaviviridae, Orthomyxoviridae, Paramyxoviridae, and Rhabdoviridae families, whereas Mda-5 is involved in the response to Picornaviridae (4). The ligand for RIG-I has been identified as a 5Ј triphosphate moiety on single-or double-stranded RNA (5, 6); the molecular ligand for Mda-5 is unknown. Following ligand engagement, these intracellular sensors signal through caspase activation and recruitment domains to activate the adaptor, interferon-␤ promoter stimulator-1 (IPS-1/MAVS/ VISA/Cardif) (7-10). IPS-1 activates inhibitor of B kinase (IKK)-␣, IKK-␤, IKK-⑀, and Tank-binding kinase 1 to phosphorylate transcription factors, including activating transcription factor-2/c-Jun, NF-B, and interferon regulatory factor-3 (IRF-3), which direct transcription of antiviral g...

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