Abstract
BackgroundThe replication cycle of most pathogens, including influenza viruses, is perfectly adapted to the metabolism and signal transduction pathways of host cells. After infection, influenza viruses activate several cellular signaling cascades that support their propagation but suppress those that interfere with viral replication. Accumulation of viral RNA plays thereby a central role. Its sensing by the pattern recognition receptors of the host cells leads to the activation of several signal transduction waves that result in induction of genes, responsible for the cellular innate immune response. Type I interferon (IFN) genes and interferon-stimulated genes (ISG) coding for antiviral-acting proteins, such as MxA, OAS-1 or PKR, are primary targets of these signaling cascades. β- and γ-catenin are closely related armadillo repeat-containing proteins with dual roles. At the cell membrane they serve as adapter molecules linking cell-cell contacts to microfilaments. In the cytosol and nucleus, the proteins form a transcriptional complex with the lymphoid enhancer factor/T-cell factor (LEF/TCF), regulating the transcription of many genes, thereby controlling different cellular functions such as cell cycle progression and differentiation.ResultsIn this study, we demonstrate that β- and γ-catenin are important regulators of the innate cellular immune response to influenza A virus (IAV) infections. They inhibit viral replication in lung epithelial cells by enhancing the virus-dependent induction of the IFNB1 gene and interferon-stimulated genes. Simultaneously, the prolonged infection counteracts the antiviral effect of β- and γ-catenin. Influenza viruses suppress β-catenin-dependent transcription by misusing the RIG-I/NF-κB signaling cascade that is induced in the course of infection by viral RNA.ConclusionWe identified β- and γ-catenin as novel antiviral-acting proteins. While these factors support the induction of common target genes of the cellular innate immune response, their functional activity is suppressed by pathogen evasion.
Highlights
The replication cycle of most pathogens, including influenza viruses, is perfectly adapted to the metabolism and signal transduction pathways of host cells
Binding of IFN-β to the type I interferon receptor (IFNAR1) activates the JAK/Signal transducers and activators of transcription (STAT) signaling cascade. This results in formation of the IFN-stimulated gene factor 3 (ISGF3) protein complex consisting of the signal transducers and activators of transcription 1/2 (STAT1/2) and the interferon regulatory factor 9 (IRF9)
Accumulation of β- and γ-catenin decreases influenza A virus propagation To elucidate whether accumulation of cellular β-catenin influences viral replication, we overexpressed the protein in human lung epithelial A549 cells by plasmid transfection prior to Influenza A viruses (IAV) infection and subsequently analyzed the efficiency of viral propagation
Summary
The replication cycle of most pathogens, including influenza viruses, is perfectly adapted to the metabolism and signal transduction pathways of host cells. The RNA accumulating viral 5′-triphosphate RNA [8,9], resulting in the activation of the first line of defense, the type I interferon (IFN) response This comprises the expression of IFN-α/β and the subsequent transcriptional activation of interferon-stimulated genes (ISG) [10]. Binding of IFN-β to the type I interferon receptor (IFNAR1) activates the JAK/STAT signaling cascade This results in formation of the IFN-stimulated gene factor 3 (ISGF3) protein complex consisting of the signal transducers and activators of transcription 1/2 (STAT1/2) and the interferon regulatory factor 9 (IRF9). The translated proteins of these ISGs directly or indirectly interfere with virus replication and, limit virus spread
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