IPS1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction (original) (raw)
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IPS-1, an adaptor triggering RIG-I-and Mda5-mediated type I interferon …
Nature …, 2005
Type I interferons are central mediators for antiviral responses. Using high-throughput functional screening of interferon inducers, we have identified here a molecule we call interferon-b promoter stimulator 1 (IPS-1). Overexpression of IPS-1 induced type I interferon and interferon- ...
Signalling pathways mediating type I interferon gene expression
Microbes and Infection, 2007
Type I interferon-a/b play an essential role in immunity to viruses. While interferon-b has been used as a model of a complex promoter, many of the signalling pathways leading to interferon-b gene expression remain controversial. Recent milestones include the discovery of Toll-like receptors and RNA helicases that signal via a novel kinase complex composed of IkB kinase-i/3 or TANK binding kinase-1. This review provides a timely summary of this rapidly expanding field, focusing specifically on the various viral RNA binding molecules and their associated signalling pathways.
The Journal of biological chemistry, 2014
The interferon γ-inducible protein 16 (IFI16) has recently been linked to the detection of nuclear and cytosolic DNA during infection with herpes simplex virus-1 and HIV. IFI16 binds dsDNA via HIN200 domains and activates stimulator of interferon genes (STING), leading to TANK (TRAF family member-associated NF-κB activator)-binding kinase-1 (TBK1)-dependent phosphorylation of interferon regulatory factor (IRF) 3 and transcription of type I interferons (IFNs) and related genes. To better understand the role of IFI16 in coordinating type I IFN gene regulation, we generated cell lines with stable knockdown of IFI16 and examined responses to DNA and RNA viruses as well as cyclic dinucleotides. As expected, stable knockdown of IFI16 led to a severely attenuated type I IFN response to DNA ligands and viruses. In contrast, expression of the NF-κB-regulated cytokines IL-6 and IL-1β was unaffected in IFI16 knockdown cells, suggesting that the role of IFI16 in sensing these triggers was uniqu...
Molecular mechanisms of interferon beta gene induction
Seminars in Virology, 1995
The Type 1 interferon genes (IFNA and IFNB) have served as an important paradigm to examine the mechanisms of virus inducible gene expression. In particular, IFNB has been amenable to reverse genetic approaches for the analysis of transcriptional activation. The DNA sequences that regulate IFNB gene transcription are located within a 110 nucleotide region, immediately upstream of the structural gene and consist of multiple, overlapping positive and negative regulatory domains essential for virus-induced activation and/or repression of the promoter. The positive regulatory domains I and III (PRDI and PRDIII)
Journal of Virology, 2002
functions as a key activator of the immediate-early alpha/beta interferon (IFN) genes, as well as the RANTES chemokine gene. In the present study, a tetracycline-inducible expression system expressing a constitutively active form of IRF-3 (IRF-3 5D) was combined with DNA microarray analysis to identify target genes regulated by IRF-3. Changes in mRNA expression profiles of 8,556 genes were monitored after Tet-inducible expression of IRF-3 5D. Among the genes upregulated by IRF-3 were transcripts for several known IFN-stimulated genes (ISGs). Subsequent analysis revealed that IRF-3 directly induced the expression of ISG56 in an IFN-independent manner through the IFN-stimulated responsive elements (ISREs) of the ISG56 promoter. These results demonstrate that, in addition to its role in the formation of a functional immediate-early IFN- enhanceosome, IRF-3 is able to discriminate among ISRE-containing genes involved in the establishment of the antiviral state as a direct response to virus infection.
Proceedings of the National Academy of Sciences, 1998
The family of interferon (IFN) regulatory factors (IRFs) encodes DNA-binding transcription factors, some of which function as modulators of virus-induced signaling. The IRF-3 gene is constitutively expressed in many tissues and cell types, and neither virus infection nor IFN treatment enhances its transcription. In infected cells, however, IRF-3 protein is phosphorylated at the carboxyl terminus, which facilitates its binding to the CBP͞p300 coactivator.
Journal of Biological Chemistry, 2008
Interferon regulatory factor 3 (IRF-3) undergoes phosphorylation-induced activation in virus-infected cells and plays an important role in the antiviral innate immune response. The E3L protein encoded by vaccinia virus is known to impair phosphorylation and activation of IRF-3. Kinases in addition to IB kinase-related kinases are implicated in the IRF-3-dependent antiviral response. To test in human cells the role of the protein kinase regulated by RNA (PKR) in IRF-3 activation, HeLa cells made stably deficient in PKR using an RNA interference strategy were compared with PKR-sufficient cells. Rapid phosphorylation and nuclear accumulation of IRF-3 were detected in PKR-sufficient cells following infection with E3L deletion mutant (⌬E3L) virus. By contrast, the full IRF-3 activation response was largely abolished in PKR-deficient cells. The ⌬E3L virus-induced IRF-3 activation seen in PKR-sufficient cells was diminished by treatment with cytosine -D-arabinofuranoside. Furthermore, the vaccinia mutant ts23, which displays increased viral double-stranded RNA production at 39°C, induced PKR-dependent IRF-3 phosphorylation at 39°C but not at 31°C. Both IRF-3 phosphorylation and cell apoptosis induced by infection with ⌬E3L virus were dependent upon RIG-I-like receptor signal transduction components, including the adapter IPS-1. These data suggest that PKR facilitates the host innate immune response and apoptosis in virus-infected cells by mediating IRF-3 activation through the mitochondrial IPS-1 signal transduction pathway.