Interferon regulatory factor 3 (IRF3) is known to participate in the transcriptional induction of interferon (IFN) alpha and IFNbeta genes, as well as of a number of interferon-stimulated genes (ISGs), as a result of viral infection.
The antiviral cytokine IFN-alpha/beta (IFN type I) produced following viral infection as a result of activation of NF-kappaB or IRF-3 or both exerts an antiviral state by inducing the Janus kinases/signal transducer and activator (Jak-Stat) pathway.
Herein, we report the identification of a novel protein termed MAVS (mitochondrial antiviral signaling), which mediates the activation of NF-kappaB and IRF 3 in response to viral infection.
Beta interferon (IFN-beta) gene expression in response to virus infection relies on the dynamic assembly of a multiprotein enhanceosome complex that is initiated by the activation of two inducible transcription factors, interferon regulatory factor 3 (IRF3) and NF-kappaB.
Viral signaling through retinoic acid-inducible gene-I (RIG-I) and its adaptor protein, IFN promoter-stimulator 1 (IPS-1), activates IFN regulatory factor-3 (IRF-3) and the host IFN-alpha/beta response that limits virus infection.
Although functional activation of IRF3 by viral infection is relatively well documented, the biological role and regulatory mechanism underlying cell growth inhibition by IRF3 are poorly understood.
Along with IRF3 and IRF7, NSP1 was found to induce the degradation of IRF5, a factor that upregulates IFN expression and that is involved in triggering apoptosis during viral infection.
IRF-3 depletion was dependent on a productive HIV-1 replication cycle and caused the specific disruption of Toll-like receptor and RIG-I-like receptor innate immune signaling that rendered cells permissive to secondary virus infection.
Viral infection activates transcription factors NF-kappaB and IRF3, which collaborate to induce type I interferons (IFNs) and elicit innate antiviral response.
Our results indicate that infection with amplicons triggered an interferon (IFN)-regulatory factors 3 and 7 (IRF3/7)-dependent antiviral response, rendered the cells resistant to vesicular stomatitis virus infection and induced significant changes in the pattern of cellular gene expression, including the upregulation of Toll-like receptor 3 (TLR3), IRF7 and IFN-stimulated genes (ISGs).
Promyelocytic leukaemia zinc finger protein (ZBTB16) was the most profoundly upregulated gene in the malignant cell population, while interferon regulatory factor 3 (IRF3) and interferon-induced protein 35 (IFI35), which are important elements of the cellular response to viral infection, were significantly downregulated.
While previous work suggests that HCMV envelope glycoprotein B is responsible for initiating this reaction, the signaling pathways stimulated by virus infection that lead to IRF3 phosphorylation have largely been uncharacterized.
Interferon regulatory factor 3 (IRF-3) is one of the master transcription factors involved in the stringent regulation of interferon production following virus infection.
We report that the transcription factor IRF3 plays a central role in the negative regulation of interferon-β (IFNβ) expression during both acute and persistent (chronic) virus infections.
Our study revealed a crucial region of the HCV core protein, basic amino acid region 1 (BR1), to inhibit IRF-3 dimerization as well as its phosphorylation induced by NDV infection and poly (I:C), thus interfering with IRF-3 activation.
Accordingly, the arenavirus nucleoprotein (NP) was shown to block activation and nuclear translocation of interferon regulatory factor 3 (IRF3) in response to virus infection.
These results point to SIN replication-mediated activation of IRF3, independent of mTOR function, when host protein synthesis is severely suppressed by virus infection.
Because the absence of interferon regulatory factor 3 (IRF3) does not increase the plaque formation efficiency of ICP0-null mutant HSV-1, we speculate that IFI16 contributes to cell-mediated restriction of HSV-1 in a manner that is separable from its roles in IRF3-mediated interferon induction, but that may be linked to the PML NB response to viral infection.
Transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κB (NFκB) are activated by external stimuli, including virus infection, to translocate to the nucleus and bind genomic targets important for immunity and inflammation.
Goose RIG-I transfected 293T/17 cells were then tested for the response to NDV infection, resulting in up-regulated activity of IFN-β promoter, and mRNA levels of IRF-3 and IFIT1, but decreased virus titer.