Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05412 (c-Jun)
 11,453 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have identified a virus-activated factor (VAF) that binds to a regulatory element shared by different virus-inducible genes. We provide evidence that VAF contains two members of the interferon regulatory factor (IRF) family of transcriptional activator proteins (IRF-3 and IRF-7), as well as the transcriptional coactivator proteins p300 and CBP. Remarkably, VAF, as well as recombinant IRF-3 and IRF-7 proteins, binds very weakly to the interferon-beta (IFN-beta) gene promoter in vitro. However, in virus-infected cells, both proteins are recruited to the endogenous IFN-beta promoter as part of a protein complex that includes ATF-2/c-Jun and NF-kappa B. These observations provide a unique example of the coordinate activation of multiple transcriptional activator proteins and their highly cooperative assembly into a transcriptional enhancer complex in vivo.
 ...
PMID:Virus infection induces the assembly of coordinately activated transcription factors on the IFN-beta enhancer in vivo. 966 Sep 35

The mechanisms of cellular recognition for virus infection remain poorly understood despite the wealth of information regarding the signaling events and transcriptional responses that ensue. Host cells respond to viral infection through the activation of multiple signaling cascades, including the activation of NF-kappaB, c-Jun/ATF-2 (AP-1), and the interferon regulatory factors (IRFs). Although viral products such as double-stranded RNA (dsRNA) and the processes of viral binding and fusion have been implicated in the activation of NF-kappaB and AP-1, the mechanism(s) of IRF-1, IRF-3, and IRF-7 activation has yet to be fully elucidated. Using recombinant measles virus (MeV) constructs, we now demonstrate that phosphorylation-dependent IRF-3 activation represents a novel cellular detection system that recognizes the MeV nucleocapsid structure. At low multiplicities of infection, IRF-3 activation is dependent on viral transcription, since UV cross-linking and a deficient MeV containing a truncated polymerase L gene failed to induce IRF-3 phosphorylation. Expression of the MeV nucleocapsid (N) protein, without the requirement for any additional viral proteins or the generation of dsRNA, was sufficient for IRF-3 activation. In addition, the nucleocapsid protein was found to associate with both IRF-3 and the IRF-3 virus-activated kinase, suggesting that it may aid in the colocalization of the kinase and the substrate. Altogether, this study suggests that IRF-3 recognizes nucleocapsid structures during the course of an MeV infection and triggers the induction of interferon production.
 ...
PMID:Recognition of the measles virus nucleocapsid as a mechanism of IRF-3 activation. 1190 5

Interferon regulatory factor (IRF)-7 is activated in response to virus infection and stimulates the transcription of a set of cellular genes involved in host antiviral defense. The mechanism by which IRF-7 is activated and cooperates with other transcription factors is not fully elucidated. Activation of IRF-7 results from a conformational change triggered by the virus-dependent phosphorylation of its C terminus. This conformational change leads to dimerization, nuclear accumulation, DNA-binding, and transcriptional transactivation. Here we show that activation of IRF-7, like that of IRF-3, is dependent on modifications of two distinct sets of Ser/Thr residues. Moreover, we show that different virus-inducible cis-acting elements display requirements for specific IRFs. In particular, the virus-responsive element of the ISG15 gene promoter can be activated by either IRF-3 or IRF-7 alone, whereas the P31 element of the interferon-beta gene is robustly activated only when IRF-3, IRF-7, and the p300/CBP coactivators are all present. Furthermore, we find that IRF-7 interacts with four distinct regions of p300/CBP. These interactions not only stimulate the intrinsic transcriptional activity of IRF-7, but they are also indispensable for its ability to strongly synergize with other transcription factors, including c-Jun and IRF-3.
 ...
PMID:Interferon regulatory factor-7 synergizes with other transcription factors through multiple interactions with p300/CBP coactivators. 1260 99

Rapid induction of type I interferon expression, a central event in establishing the innate antiviral response, requires cooperative activation of numerous transcription factors. Although signaling pathways that activate the transcription factors nuclear factor kappaB and ATF-2/c-Jun have been well characterized, activation of the interferon regulatory factors IRF-3 and IRF-7 has remained a critical missing link in understanding interferon signaling. We report here that the IkappaB kinase (IKK)-related kinases IKKepsilon and TANK-binding kinase 1 are components of the virus-activated kinase that phosphorylate IRF-3 and IRF-7. These studies illustrate an essential role for an IKK-related kinase pathway in triggering the host antiviral response to viral infection.
 ...
PMID:Triggering the interferon antiviral response through an IKK-related pathway. 1467 33

Interferons (IFN)s are involved in numerous immune interactions during viral infections and contribute to both induction and regulation of innate and adaptive antiviral mechanisms. IFNs play a pivotal rule in the outcome of a viral infection, as demonstrated by the impaired resistance against different viruses in mice deficient for the receptors IFNAR-2 and IFNGR. During viral infections, IFNs are involved in numerous immune interactions as inducers, regulators, and effectors of both innate and adaptive antiviral mechanisms. IFN-alpha/beta is produced rapidly when viral factors, such as envelope glycoproteins, CpG DNA, or dsRNA, interact with cellular pattern-recognition receptors (PRRs), such as mannose receptors, toll-like receptors (TLRs), and cytosolic receptors. These host-virus interactions signal downstream to activate transcription factors needed to achieve expression from IFN-alpha/beta genes. These include IFN regulatory factor-3 (IRF-3), IRF-5, IRF-7, c-Jun/ATF-2, and NF-kappaB. In contrast, IFN-gamma is induced by receptor-mediated stimulation or in response to early produced cytokines, including interleukin-2 (IL-12), IL-18, and IFN-alpha/beta, or by stimulation through T cell receptors (TCRs) or natural killer (NK) cell receptors. IFNs signal through transmembrane receptors, activating mainly Jak-Stat pathways but also other signal transduction pathways. Cytokine and TCR-induced IFN-gamma expression uses distinct signal transduction pathways involving such transcription factors as NFAT, Stats and NF-kappaB. This results in induction and activation of numerous intrinsic antiviral factors, such as RNA-activated protein kinase (PKR), the 2-5A system, Mx proteins, and several apoptotic pathways. In addition, IFNs modulate distinct aspects of both innate and adaptive immunity. Thus, IFN-alpha/beta and IFN-gamma affect activities of macrophages, NK cells, dendritic cells (DC), and T cells by enhancing antigen presentation, cell trafficking, and cell differentiation and expression profiles, ultimately resulting in enhanced antiviral effector functions. This review focuses on the latest findings regarding induction and regulation of IFNs, primarily during the early phase of an antiviral immune response. Both cellular and molecular aspects are discussed from the perspective of host-virus interactions.
 ...
PMID:Induction and regulation of IFNs during viral infections. 1532 Sep 58

The interferon-beta promoter has been studied extensively as a model system for combinatorial transcriptional regulation. In virus-infected cells the transcription factors ATF-2, c-Jun, interferon regulatory factor (IRF)-3, IRF-7 and NF-kappaB, and the coactivators p300/CBP play critical roles in the activation of this and other promoters. It remains unclear, however, why most other combinations of AP-1, IRF and Rel proteins fail to activate the interferon-beta gene. Here we have explored how different IRFs may cooperate with other factors to activate transcription. First we showed in undifferentiated embryonic carcinoma cells that ectopic expression of either IRF-3 or IRF-7, but not IRF-1, was sufficient to allow virus-dependent activation of the interferon-beta promoter. Moreover, the activity of IRF-3 and IRF-7 was strongly affected by promoter context, with IRF-7 preferentially being recruited to the natural interferon-beta promoter. We fully reconstituted activation of this promoter in insect cells. Maximal synergy required IRF-3 and IRF-7 but not IRF-1, and was strongly dependent on the presence of p300/CBP, even when these coactivators only modestly affected the activity of each factor by itself. These results suggest that specificity in activation of the interferon-beta gene depends on a unique promoter context and on the role played by coactivators as architectural factors.
 ...
PMID:Mechanism for transcriptional synergy between interferon regulatory factor (IRF)-3 and IRF-7 in activation of the interferon-beta gene promoter. 1535 47

Transcriptional activation of the interferon-beta (IFN-beta) gene requires assembly of an enhanceosome containing the transcription factors ATF-2/c-Jun, IRF-3/IRF-7, NF-kappaB and HMGI(Y). These factors cooperatively bind a composite DNA site and activate expression of the IFN-beta gene. The 3.0 A crystal structure of the DNA-binding domains of ATF-2/c-Jun and two IRF-3 molecules in a complex with 31 base pairs (bp) of the PRDIV-PRDIII region of the IFN-beta enhancer shows that association of the four proteins with DNA creates a continuous surface for the recognition of 24 bp. The structure, together with in vitro binding studies and protein mutagenesis, shows that protein-protein interactions are not critical for cooperative binding. Instead, cooperativity arises mainly through nucleotide sequence-dependent structural changes in the DNA that allow formation of complementary DNA conformations. Because the binding sites overlap on the enhancer, the unit of recognition is the entire nucleotide sequence, not the individual subsites.
 ...
PMID:Crystal structure of ATF-2/c-Jun and IRF-3 bound to the interferon-beta enhancer. 1551 Feb 18

Transcriptional activation of the interferon-beta (IFN-beta) gene requires assembly of an enhanceosome containing ATF-2/c-Jun, IRF-3/IRF-7, and NFkappaB. These factors bind cooperatively to the IFN-beta enhancer and recruit coactivators and chromatin-remodeling proteins to the IFN-beta promoter. We describe here a crystal structure of the DNA-binding domains of IRF-3, IRF-7, and NFkappaB, bound to one half of the enhancer, and use a previously described structure of the remaining half to assemble a complete picture of enhanceosome architecture in the vicinity of the DNA. Association of eight proteins with the enhancer creates a continuous surface for recognizing a composite DNA-binding element. Paucity of local protein-protein contacts suggests that cooperative occupancy of the enhancer comes from both binding-induced changes in DNA conformation and interactions with additional components such as CBP. Contacts with virtually every nucleotide pair account for the evolutionary invariance of the enhancer sequence.
 ...
PMID:An atomic model of the interferon-beta enhanceosome. 1757 24

Interferon regulatory factors (IRF)-3 and IRF-7 are master transcriptional factors that regulate type I IFN gene (IFN-alpha/beta) induction and innate immune defenses after virus infection. Prior studies in mice with single deletions of the IRF-3 or IRF-7 genes showed increased vulnerability to West Nile virus (WNV) infection. Whereas mice and cells lacking IRF-7 showed reduced IFN-alpha levels after WNV infection, those lacking IRF-3 or IRF-7 had relatively normal IFN-b production. Here, we generated IRF-3(-/-)x IRF-7(-/-) double knockout (DKO) mice, analyzed WNV pathogenesis, IFN responses, and signaling of innate defenses. Compared to wild type mice, the DKO mice exhibited a blunted but not abrogated systemic IFN response and sustained uncontrolled WNV replication leading to rapid mortality. Ex vivo analysis showed complete ablation of the IFN-alpha response in DKO fibroblasts, macrophages, dendritic cells, and cortical neurons and a substantial decrease of the IFN-beta response in DKO fibroblasts and cortical neurons. In contrast, the IFN-beta response was minimally diminished in DKO macrophages and dendritic cells. However, pharmacological inhibition of NF-kappaB and ATF-2/c-Jun, the two other known components of the IFN-beta enhanceosome, strongly reduced IFN-beta gene transcription in the DKO dendritic cells. Finally, a genetic deficiency of IPS-1, an adaptor involved in RIG-I- and MDA5-mediated antiviral signaling, completely abolished the IFN-beta response after WNV infection. Overall, our experiments suggest that, unlike fibroblasts and cortical neurons, IFN-beta gene regulation after WNV infection in myeloid cells is IPS-1-dependent but does not require full occupancy of the IFN-beta enhanceosome by canonical constituent transcriptional factors.
 ...
PMID:Induction of IFN-beta and the innate antiviral response in myeloid cells occurs through an IPS-1-dependent signal that does not require IRF-3 and IRF-7. 1979 31