Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.10 (IKK)
4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Viral infection or TLR3 engagement causes activation of the transcription factors IRF-3 and NF-kappaB, which collaborate to induce transcription of type I IFN genes. IKKepsilon and TBK1 are two IKK-related kinases critically involved in virus- and TLR3-triggered activation of IRF-3. We identified a protein termed SIKE (for Suppressor of IKKepsilon) that interacts with IKKepsilon and TBK1. SIKE is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection or TLR3 stimulation. Overexpression of SIKE disrupted the interactions of IKKepsilon or TBK1 with TRIF, RIG-I and IRF-3, components in virus- and TLR3-triggered IRF-3 activation pathways, but did not disrupt the interactions of TRIF with TRAF6 and RIP, components in TLR3-triggered NF-kappaB activation pathway. Consistently, overexpression of SIKE inhibited virus- and TLR3-triggered interferon-stimulated response elements (ISRE) but not NF-kappaB activation. Knockdown of SIKE potentiated virus- and TLR3-triggered ISRE but not NF-kappaB activation. Moreover, overexpression of SIKE inhibited IKKepsilon- and TBK1-mediated antiviral response. These findings suggest that SIKE is a physiological suppressor of IKKepsilon and TBK1 and plays an inhibitory role in virus- and TLR3-triggered IRF-3 but not NF-kappaB activation pathways.
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PMID:SIKE is an IKK epsilon/TBK1-associated suppressor of TLR3- and virus-triggered IRF-3 activation pathways. 1628 Oct 57

IFN regulatory factor-3 is a transcription factor that is required for the rapid induction of type I IFNs in the innate antiviral response. Two noncanonical IkappaB kinase (IKK) family members, IKKepsilon and TRAF family-associated NF-kappaB activator-binding kinase-1, have been shown to phosphorylate IFN regulatory factor-3 and are critically involved in virus-triggered and TLR3-mediated signaling leading to induction of type I IFNs. In yeast two-hybrid screens for potential IKKepsilon-interacting proteins, we identified Ret finger protein (RFP) as an IKKepsilon-interacting protein. Coimmunoprecipitation experiments indicated that RFP interacted with IKKepsilon and TRAF family-associated NF-kappaB activator-binding kinase-1 as well as the two canonical IKK family members, IKKbeta and IKKalpha. RFP inhibited activation of the IFN-stimulated response element and/or NF-kappaB mediated by the IKK family members and triggered by TNF, IL-1, polyinosinic-polycytidylic acid (ligand for TLR3), and viral infection. Moreover, knockdown of RFP expression by RNA interference-enhanced activation of IFN-stimulated response element and/or NF-kappaB triggered by polyinosinic-polycytidylic acid, TNF, and IL-1. Taken together, our findings suggest that RFP negatively regulates signaling involved in the antiviral response and inflammation by targeting the IKKs.
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PMID:The Ret finger protein inhibits signaling mediated by the noncanonical and canonical IkappaB kinase family members. 1639 95

A genome-wide phenotype screen was used to identify factors and pathways that induce proliferation of human umbilical vein endothelial cells (HUVEC). HUVEC proliferation is a recognized marker for factors that modulate vascularization. Screening "hits" included known proangiogenic factors, such as VEGF, FGF1, and FGF2 and additional factors for which a direct association with angiogenesis was not previously described. These include the kinase TBK1 as well as Toll-like receptor adaptor molecule and IFN regulatory factor 3. All three proteins belong to one signaling pathway that mediates induction of gene expression, including a mixture of secreted factors, which, in concert, mediate proliferative activity toward endothelial cells. TBK1 as the "trigger" of this pathway is induced under hypoxic conditions and expressed at significant levels in many solid tumors. This pattern of expression and the decreased expression of angiogenic factors in cultured cells upon RNA-interference-mediated ablation suggests that TBK1 is important for vascularization and subsequent tumor growth and a target for cancer therapy.
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PMID:Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway. 1653 15

The Toll-like receptor (TLR) family has important roles in microbial recognition and dendritic cell activation. TLRs 7 and 9 can recognize nucleic acids and trigger signalling cascades that activate plasmacytoid dendritic cells to produce interferon-alpha (IFN-alpha) (refs 7, 8). TLR7/9-mediated dendritic cell activation is critical for antiviral immunity but also contributes to the pathogenesis of systemic lupus erythematosus, a disease in which serum IFN-alpha levels are elevated owing to plasmacytoid dendritic cell activation. TLR7/9-induced IFN-alpha induction depends on a molecular complex that contains a TLR adaptor, MyD88, and IFN regulatory factor 7 (IRF-7) (refs 10-14), but the underlying molecular mechanisms are as yet unknown. Here we show that IkappaB kinase-alpha (IKK-alpha) is critically involved in TLR7/9-induced IFN-alpha production. TLR7/9-induced IFN-alpha production was severely impaired in IKK-alpha-deficient plasmacytoid dendritic cells, whereas inflammatory cytokine induction was decreased but still occurred. Kinase-deficient IKK-alpha inhibited the ability of MyD88 to activate the Ifna promoter in synergy with IRF-7. Furthermore, IKK-alpha associated with and phosphorylated IRF-7. Our results identify a role for IKK-alpha in TLR7/9 signalling, and highlight IKK-alpha as a potential target for manipulating TLR-induced IFN-alpha production.
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PMID:IkappaB kinase-alpha is critical for interferon-alpha production induced by Toll-like receptors 7 and 9. 1661 87

Members of the IFN regulatory factor (IRF) family regulate gene expression critical to immune response, hemopoiesis, and proliferation. Although related by homology at their N-terminal DNA-binding domain, they display individual functional properties. The distinct properties result from differences in regulated expression, response to activating signals, and interaction with DNA regulatory elements. IRF-3 is expressed ubiquitously and is activated by serine phosphorylation in response to viral infection or TLR signaling. Evidence indicates that the kinases TANK-binding kinase 1 and inhibitor of NF-kappaB kinase-epsilon specifically phosphorylate and thereby activate IRF-3. We evaluated the contribution of another member of the IRF family, IRF-5, during viral infection since prior studies provided varied results. Analysis of phosphorylation, nuclear translocation, dimerization, binding to CREB-binding protein, recognition of DNA, and induction of gene expression were used comparatively with IRF-3 as a measure of IRF-5 activation. IRF-5 was not activated by viral infection; however, expression of TANK-binding kinase 1 or inhibitor of NF-kappaB kinase-epsilon did provide clear activation of IRF-5. IRF-5 is therefore distinct in its activation profile from IRF-3. However, similar to the biological effects of IRF-3 activation, a constitutively active mutation of IRF-5 promoted apoptosis. The apoptosis was inhibited by expression of Bcl-x(L) but not a dominant-negative mutation of the Fas-associated death domain. These studies support the distinct activation profiles of IRF-3 in comparison to IRF-5, but reveal a potential shared biological effect.
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PMID:Differential activation of IFN regulatory factor (IRF)-3 and IRF-5 transcription factors during viral infection. 1675 92

Type I interferons (IFNalpha/beta) are central mediators for antiviral responses. Using a functional cloning strategy, we have identified a molecule designated IPS-1. IPS-1 overexpression caused antiviral responses by producing type I IFN and IFN-inducible genes through activation of IRF3, IRF7 and NF-kappaB. TBK1 and IKKi protein kinases were required for the IPS-1-mediated IFN induction. IPS-1 contains an N-terminal caspase recruiting domain (CARD)-like structure that mediates interaction with the CARD of RIG-I and Mda5, cytoplasmic RNA helicases sensing RNA viruses. Reduction of IPS-1 by siRNA blocked IFN induction by virus infection. Thus, IPS-1 is an adapter that mediates RIG-I- and Mda5-dependent antiviral responses.
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PMID:[Role of IPS-1 in type I IFN induction]. 1684 92

Type I IFN (IFN-alpha/beta) have important biological functions ranging from immune cell development and activation, to tumor cell killing and most importantly inhibition of virus replication. Following viral infection or activation of Toll-like receptors (TLRs) via distinct ligands, IFN-alpha/beta are produced. Two members of the interferon regulatory factor (IRF) family - IRF-3 and IRF-7 - are the major modulators of IFN gene expression. Activation of IRF-3 and IRF-7 by TBK1/IKKvarepsilon mediated phosphorylation promotes IFN gene expression and potentiates the production of IFN responsive genes important to the development of an effective antiviral immune response. IFN treatment can augment anti-tumor properties and they are potentially key players in cancer therapy. For example, adoptive transfer of IFN-gamma-activated macrophages can mediate tumor cell killing via direct cell-cell contact, as well as release of soluble cytotoxic pro-inflammatory molecules. A recent study investigated whether IRF-3 and IRF-7 could mediate the acquisition of new anti-tumor effector functions in macrophages. Adenovirus mediated transduction of the active form of IRF-7 into primary macrophages resulted in the production of type I IFN, upregulation of target genes including TRAIL and increased tumoricidal activity of macrophages; in contrast, the active form of IRF-3 led to induction of cell death. These studies indicate that IRF-7 transduced macrophages may be an attractive candidate for in vivo adoptive therapy of cancer.
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PMID:Distinct functions of IRF-3 and IRF-7 in IFN-alpha gene regulation and control of anti-tumor activity in primary macrophages. 1684 91

Recent advances in the understanding of the signaling pathways leading to the host antiviral response to hepatitis C virus (HCV), the mechanisms used by HCV to evade the immune response, and the development of small molecule inhibitors of HCV have generated optimism that novel therapeutic approaches to control HCV disease may soon be available. HCV infection is detected by the cytoplasmic, RNA helicase RIG-I that plays an essential role in signaling to the host antiviral response. Recently the adapter molecule that links RIG-I sensing of incoming viral RNA to downstream signaling and gene activation events was characterized by four different groups: MAVS/IPS-1-1/VISA/Cardif contains an amino-terminal CARD domain and carboxyl-terminal mitochondrial transmembrane sequence that localizes to the mitochondrial membrane. Furthermore, the hepatitis C virus NS3-4A protease complex specifically targets MAVS/IPS-1/VISA/Cardif for cleavage as part of its immune evasion strategy. Using a combination of biochemical analysis, subcellular fractionation and confocal microscopy, we demonstrate that: (1) NS3-4A cleavage of MAVS/IPS-1/VISA/Cardif causes relocation from the mitochondrial membrane to the cytosolic fraction, resulting in disruption of signaling to the antiviral immune response; (2) disruption requires a function NS3-4A protease; (3) a point mutant of MAVS/IPS-1/VISA/Cardif (Cys508Ala) is not cleaved from the mitochondria by active protease; and (4) the virus-induced IKK epsilon kinase, but not TBK1, co-localizes strongly with MAVS at the mitochondrial membrane and the localization of both molecules is disrupted by NS3-4A expression. These observations provide an outline of the mechanism by which HCV evades the IFN antiviral response.
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PMID:Recruitment of an interferon molecular signaling complex to the mitochondrial membrane: disruption by hepatitis C virus NS3-4A protease. 1687 65

The NF-kappaB transcription factors are key regulators of immunomodulatory, cell cycle, and developmental gene regulation. NF-kappaB activity is mainly regulated through the phosphorylation of IkappaB by the IkappaB kinase (IKK) complex IKKalphabetagamma, leading to proteasome-mediated degradation of IkappaB, nuclear translocation of NF-kappaB dimers, DNA binding, and gene induction. Additionally, direct posttranslational modifications of NF-kappaB p65 and cRel subunits involving C-terminal phosphorylation has been demonstrated. The noncanonical IKK-related homologs, TNFR-associated factor family member-associated NF-kappaB activator (TANK)-binding kinase (TBK)1 and IKKepsilon, are also thought to play a role in NF-kappaB regulation, but their functions remain unclear. TBK1 and IKKepsilon were recently described as essential regulators of IFN gene activation through direct phosphorylation of the IFN regulatory factor-3 and -7 transcription factors. In the present study, we sought to determine whether IKKepsilon and TBK1 could modulate cRel activity via phosphorylation. TBK1 and IKKepsilon directly phosphorylate the C-terminal domain of cRel in vitro and in vivo and regulate nuclear accumulation of cRel, independently of the classical IkappaB/IKK pathway. IkappaBalpha degradation is not affected, but rather IKKepsilon-mediated phosphorylation of cRel leads to dissociation of the IkappaBalpha-cRel complex. These results illustrate a previously unrecognized aspect of cRel regulation, controlled by direct IKKepsilon/TBK1 phosphorylation.
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PMID:Nuclear accumulation of cRel following C-terminal phosphorylation by TBK1/IKK epsilon. 1688 14

Toll-like receptors (TLRs) play an important role in recognition of microbial components and induction of innate immunity. The microbial components trigger the activation of two downstream signaling pathways of TLRs; MyD88- and/or TRIF-dependent pathways leading to activation of NF-kappaB. (-)-Epigallocatechin-3-gallate (EGCG), a flavonoid found in green tea, is known to inhibit NF-kappaB activation induced by many pro-inflammatory stimuli. EGCG was shown to inhibit the activity of IKKbeta which is the key kinase in the canonical pathway for NF-kappaB activation in MyD88-dependent pathway of TLRs. However, it is not known whether EGCG inhibits TRIF-dependent pathway through which more than 70% of lipopolysaccharide (LPS)-induced genes are regulated. Therefore, we attempted to identify the molecular target of EGCG in TRIF-dependent pathways of TLR3 and TLR4. EGCG inhibited the activation of IFN regulatory factor 3 (IRF3) induced by LPS, poly[I:C], or the overexpression of TRIF. The inhibition of IRF3 activation by EGCG was mediated through the suppression of the kinase activity of TBK1. However, EGCG did not inhibit activation of IRF3 induced by overexpression of constitutively active IRF3. These results suggest that the molecular target of EGCG is TBK1 in TRIF-dependent signaling pathways of TLR3 and TLR4. Therefore, our results suggest that green tea flavonoids can modulate both MyD88- and TRIF-dependent signaling pathways of TLRs and subsequent inflammatory target gene expression.
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PMID:Suppression of MyD88- and TRIF-dependent signaling pathways of Toll-like receptor by (-)-epigallocatechin-3-gallate, a polyphenol component of green tea. 1689 Feb 9


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