ABSTRACT
The poly(ADP-ribose) polymerases (PARPs) participate in many biological and pathological processes. Here we report that the PARP-13 shorter isoform (ZAPS), rather than the full-length protein (ZAP), was selectively induced by 5'-triphosphate-modified RNA (3pRNA) and functioned as a potent stimulator of interferon responses in human cells mediated by the RNA helicase RIG-I. ZAPS associated with RIG-I to promote the oligomerization and ATPase activity of RIG-I, which led to robust activation of IRF3 and NF-κB transcription factors. Disruption of the gene encoding ZAPS resulted in impaired induction of interferon-α (IFN-α), IFN-ß and other cytokines after viral infection. These results indicate that ZAPS is a key regulator of RIG-I signaling during the innate antiviral immune response, which suggests its possible use as a therapeutic target for viral control.
Subject(s)
Avulavirus Infections/metabolism , DEAD-box RNA Helicases/metabolism , Newcastle disease virus/physiology , Orthomyxoviridae Infections/metabolism , Orthomyxoviridae/physiology , Poly(ADP-ribose) Polymerases/metabolism , Protein Isoforms/metabolism , Avulavirus Infections/immunology , DEAD Box Protein 58 , DEAD-box RNA Helicases/immunology , Gene Expression Regulation/genetics , Gene Expression Regulation/immunology , HEK293 Cells , Humans , Immunity, Innate , Interferon Type I/genetics , Interferon Type I/metabolism , Newcastle disease virus/pathogenicity , Orthomyxoviridae/pathogenicity , Orthomyxoviridae Infections/immunology , Poly I-C/immunology , Poly(ADP-ribose) Polymerases/genetics , Poly(ADP-ribose) Polymerases/immunology , Protein Isoforms/genetics , Protein Isoforms/immunology , RNA, Small Interfering/genetics , RNA-Binding Proteins , Receptors, Immunologic , Signal Transduction/genetics , Signal Transduction/immunology , Virus Replication/geneticsSubject(s)
DNA-Binding Proteins/immunology , DNA/immunology , Immunity, Innate/immunology , RNA/immunology , Toll-Like Receptor 3/immunology , Toll-Like Receptor 9/immunology , Animals , DEAD Box Protein 58 , DEAD-box RNA Helicases/immunology , Humans , Interferon-Induced Helicase, IFIH1 , RNA-Binding Proteins , Receptors, Immunologic , Signal Transduction , Toll-Like Receptor 7/immunologyABSTRACT
Infection of influenza A virus in mammals induces hyper lung pneumonia, which often causes lethal diseases. FasL is a specific ligand of Fas, which is a type-I transmembrane protein to induce cell death. Previously, it has been reported that the hyper induction of gene expression associated with Fas signal is observed in lethal influenza A virus infection. More importantly, it was also reported that functional mutation of the FasL gene protects the host against influenza A virus infection. These observations suggest that induction of FasL signal is functionally associated with the severity of influenza. However, regulation of the induction of FasL or Fas by influenza A virus infection is still unknown. Here, we demonstrated that FasL is induced after the viral infection, and inhibition of the Fas/FasL signal by treatment with a recombinant decoy receptor for FasL (Fas-Fc) increases the survival rate of mice after lethal infection of influenza A virus as well as functional mutation of the FasL gene in gld/gld mice. In addition, the induction level of FasL gene expression in the lung was correlated with the severity of influenza. We also showed that a variety of types of cells in the lung express FasL after the viral infection. Furthermore, type-I interferon induced by the viral infection was shown to be critical for induction of FasL protein expression in the lung. These findings suggested that expression of FasL protein induced by type-I IFN on the lung cell surface is critical to determine the severity of influenza.