Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of NF-kappaB requires the inhibitor of kappaB (IkappaB) kinase (IKK) complex, which is made up of two functional kinases, IKKalpha and IKKbeta, and the scaffolding protein IKKgamma. We recently identified several interferon-gamma (IFN-gamma)-stimulated genes (ISGs) that are not induced in mouse embryonic fibroblast cells (MEFs) doubly null for the expression of IKKalpha and IKKbeta. We show here that the IFN-gamma-induced transcription of IKK-dependent ISGs requires IKKbeta but not IKKalpha. We also identify several additional IKKbeta-dependent ISGs that are induced by IFN-gamma both in MEFs and in RAW 264.7 macrophages. Many have a combination of kappaB and IFN-stimulated response elements (ISRE) in their promoters. Although the IFN-gamma-induced expression of the IKKbeta-dependent gene ip-10 is sensitive to the superrepressor (SR) of IkappaBalpha and requires the p65 subunit of NF-kappaB, IFN-gamma does not activate NF-kappaB. In summary, a distinct subset of IFN-gamma-dependent genes requires some components of the normal pathway of NF-kappaB activation without activation of NF-kappaB signaling by IFN-gamma.
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PMID:Activation of a subset of genes by IFN-gamma requires IKKbeta but not interferon-dependent activation of NF-kappaB. 1797 Jun 97

TLR3 recognizes viral dsRNA and induces antiviral immune responses. TLR3-mediated cell activation relies on Toll/IL-1R (TIR) domain-containing adaptor molecule-1 (TICAM-1, also named TIR domain-containing adaptor inducing IFN-beta or TRIF), which recruits downstream signaling molecules to activate the transcription factors IFN regulatory factor 3 (IRF-3) and NF-kappaB. The mechanisms by which TICAM-1 is activated and transmits signals remain largely unknown. In this study we show that TICAM-1 alters its distribution profile from a diffuse cytoplasmic form to a speckle-like structure in response to dsRNA. The receptor-interacting protein 1 (RIP1), a crucial signaling molecule for TICAM-1-mediated NF-kappaB activation, accumulated in the TICAM-1 speckles. In addition, NF-kappaB-activating kinase-associated protein 1 (NAP1), a downstream molecule linking TICAM-1 and the IRF-3-activating kinase TBK1 (TANK-binding kinase 1), was also recruited to the TICAM-1 speckles. Notably, a transient colocalization of TICAM-1 and TLR3 was observed before the extensive formation of the TICAM-1 speckles. Thus, the spatiotemporal mobilization of TICAM-1 in response to dsRNA and the formation of the TICAM-1 speckles containing RIP1 and NAP1 are important for the activation of the TLR3-TICAM-1 pathway.
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PMID:Spatiotemporal mobilization of Toll/IL-1 receptor domain-containing adaptor molecule-1 in response to dsRNA. 1798 77

Production of type I interferon (IFN-I) is a critical host defense triggered by pattern-recognition receptors (PRRs) of the innate immune system. Deubiquitinating enzyme A (DUBA), an ovarian tumor domain-containing deubiquitinating enzyme, was discovered in a small interfering RNA-based screen as a regulator of IFN-I production. Reduction of DUBA augmented the PRR-induced IFN-I response, whereas ectopic expression of DUBA had the converse effect. DUBA bound tumor necrosis factor receptor-associated factor 3 (TRAF3), an adaptor protein essential for the IFN-I response. TRAF3 is an E3 ubiquitin ligase that preferentially assembled lysine-63-linked polyubiquitin chains. DUBA selectively cleaved the lysine-63-linked polyubiquitin chains on TRAF3, resulting in its dissociation from the downstream signaling complex containing TANK-binding kinase 1. A discrete ubiquitin interaction motif within DUBA was required for efficient deubiquitination of TRAF3 and optimal suppression of IFN-I. Our data identify DUBA as a negative regulator of innate immune responses.
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PMID:DUBA: a deubiquitinase that regulates type I interferon production. 1799 29

Although the role of human IRF-5 in antiviral and inflammatory responses in vitro has been well characterized, much remains to be elucidated about murine IRF-5. Murine IRF-5, unlike the heavily spliced human gene, is primarily expressed as a full-length transcript, with only a single splice variant that was detected in very low levels in the bone marrow of C57BL/6J mice. This bone marrow variant contains a 288-nucleotide deletion from exons 4-6 and exhibits impaired transcriptional activity. The murine IRF-5 can be activated by both TBK1 and MyD88 to form homodimers and bind to and activate transcription of type I interferon and inflammatory cytokine genes. The importance of IRF-5 in the antiviral and inflammatory response in vivo is highlighted by marked reductions in serum levels of type I interferon and tumor necrosis factor alpha (TNFalpha) in Newcastle disease virus-infected Irf5(-)(/)(-) mice. IRF-5 is critical for TLR3-, TLR4-, and TLR9-dependent induction of TNFalpha in CD11c(+) dendritic cells. In contrast, TLR9, but not TLR3/4-mediated induction of type I IFN transcription, is dependent on IRF-5 in these cells. In addition, IRF-5 regulates TNFalpha but not type I interferon gene transcription in Newcastle disease virus-infected peritoneal macrophages. Altogether, these data reveal the cell type-specific importance of IRF-5 in MyD88-mediated antiviral pathways and the widespread role of IRF-5 in the regulation of inflammatory cytokines.
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PMID:Functional characterization of murine interferon regulatory factor 5 (IRF-5) and its role in the innate antiviral response. 1833 33

Acrolein is a highly electrophilic alpha,beta-unsaturated aldehyde present in a number of environmental sources, especially cigarette smoke. It reacts strongly with the thiol groups of cysteine residues by Michael addition and has been reported to inhibit nuclear factor-kappaB (NF-kappaB) activation by lipopolysaccharide (LPS). The mechanism by which it inhibits NF-kappaB is not clear. Toll-like receptors (TLRs) play a key role in sensing microbial components and inducing innate immune responses, and LPS-induced dimerization of TLR4 is required for activation of downstream signaling pathways. Thus, dimerization of TLR4 may be one of the first events involved in activating TLR4-mediated signaling pathways. Stimulation of TLR4 by LPS activates both myeloid differential factor 88 (MyD88)- and TIR domain-containing adapter inducing IFNbeta(TRIF)-dependent signaling pathways leading to activation of NF-kappaB and IFN-regulatory factor 3 (IRF3). Acrolein inhibited NF-kappaB and IRF3 activation by LPS, but it did not inhibit NF-kappaB or IRF3 activation by MyD88, inhibitor kappaB kinase (IKK)beta, TRIF, or TNF-receptor-associated factor family member-associated NF-kappaB activator (TANK)-binding kinase 1 (TBK1). Acrolein inhibited LPS-induced dimerization of TLR4, which resulted in the down-regulation of NF-kappaB and IRF3 activation. These results suggest that activation of TLRs and subsequent immune/inflammatory responses induced by endogenous molecules or chronic infection can be modulated by certain chemicals with a structural motif that enables Michael addition.
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PMID:Acrolein with an alpha, beta-unsaturated carbonyl group inhibits LPS-induced homodimerization of toll-like receptor 4. 1841 4

Pathogenic hantaviruses replicate within human endothelial cells and cause two diseases, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. In order to replicate in endothelial cells pathogenic hantaviruses inhibit the early induction of beta interferon (IFN-beta). Expression of the cytoplasmic tail of the pathogenic NY-1 hantavirus Gn protein is sufficient to inhibit RIG-I- and TBK1-directed IFN responses. The formation of TBK1-TRAF3 complexes directs IRF-3 phosphorylation, and both IRF-3 and NF-kappaB activation are required for transcription from the IFN-beta promoter. Here we report that the NY-1 virus (NY-1V) Gn tail inhibits both TBK1-directed NF-kappaB activation and TBK1-directed transcription from promoters containing IFN-stimulated response elements. The NY-1V Gn tail coprecipitated TRAF3 from cellular lysates, and analysis of TRAF3 deletion mutants demonstrated that the TRAF3 N terminus is sufficient for interacting with the NY-1V Gn tail. In contrast, the Gn tail of the nonpathogenic hantavirus Prospect Hill virus (PHV) failed to coprecipitate TRAF3 or inhibit NF-kappaB or IFN-beta transcriptional responses. Further, expression of the NY-1V Gn tail blocked TBK1 coprecipitation of TRAF3 and infection by NY-1V, but not PHV, blocked the formation of TBK1-TRAF3 complexes. These findings indicate that the NY-1V Gn cytoplasmic tail forms a complex with TRAF3 which disrupts the formation of TBK1-TRAF3 complexes and downstream signaling responses required for IFN-beta transcription.
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PMID:The NY-1 hantavirus Gn cytoplasmic tail coprecipitates TRAF3 and inhibits cellular interferon responses by disrupting TBK1-TRAF3 complex formation. 1861 28

JNK is a key regulator of matrix metalloproteinase production in rheumatoid arthritis. It is regulated by two upstream kinases known as MKK4 and MKK7. Previous studies demonstrated that only MKK7 is required for cytokine-mediated JNK activation and matrix metalloproteinase expression in cultured fibroblast-like synoviocytes (FLS). However, the functions of MKK4 and MKK7 in synoviocyte innate immune responses have not been determined. TNF, peptidoglycan (PGN), and LPS stimulation led to higher and more prolonged MKK7 phosphorylation compared with MKK4 in FLS. However, this pattern was reversed in poly(I-C) stimulated cells. siRNA knockdown studies showed that TNF, PGN, and LPS-induced JNK and c-Jun phosphorylation are MKK7 dependent, while poly(I-C) responses require both MKK4 and MKK7. Poly(I-C)-induced expression of IP-10, RANTES, and IFN-beta mRNA was decreased in MKK4- or MKK7-deficient FLS. However, MKK4 and MKK7 deficiency did not affect phosphorylation of IkappaB kinase-related kinases in the TLR3 signaling pathway. MKK7, but not MKK4 deficiency, significantly decreased poly(I-C)-mediated IRF3 dimerization, DNA binding, and IFN-sensitive response element-mediated gene transcription. These results were mimicked by the JNK inhibitor SP600125, indicating that JNK can directly phosphorylate IRF3. In contrast, deficiency of either MKK4 or MKK7 decreased AP-1 transcriptional activity. Therefore, JNK is differentially regulated by MKK4 and MKK7 depending on the stimulus. MKK7 is the primary activator of JNK in TNF, LPS, and PGN responses. However, TLR3 requires both MKK4 and MKK7, with the former activating c-Jun and the latter activating both c-Jun and IRF3 through JNK-dependent mechanisms.
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PMID:Synoviocyte innate immune responses: I. Differential regulation of interferon responses and the JNK pathway by MAPK kinases. 1871 96

The central role of plasmacytoid dendritic cells (pDC) in activating host immune responses stems from their high capacity to express alpha interferon (IFN-alpha) after stimulation of Toll-like receptors 7 and 9 (TLR7 and -9). This involves the adapter MyD88 and the kinases interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, and IkappaB kinase alpha (IKKalpha), which activates IFN regulatory factor 7 (IRF7) and is independent of the canonical kinases TBK1 and IKKepsilon. We have recently shown that the immunosuppressive measles virus (MV) abolishes TLR7/9/MyD88-dependent IFN induction in human pDC (Schlender et al., J. Virol. 79:5507-5515, 2005), but the molecular mechanisms remained elusive. Here, we have reconstituted the pathway in cell lines and identified IKKalpha and IRF7 as specific targets of the MV V protein (MV-V). Binding of MV-V to IKKalpha resulted in phosphorylation of V on the expense of IRF7 phosphorylation by IKKalpha in vitro and in living cells. This corroborates the role of IKKalpha as the kinase phosphorylating IRF7. MV-V in addition bound to IRF7 and to phosphomimetic IRF7 and inhibited IRF7 transcriptional activity. Binding to both IKKalpha and IRF7 required the 68-amino-acid unique C-terminal domain of V. Inhibition of TLR/MyD88-dependent IFN induction by MV-V is unique among paramyxovirus V proteins and should contribute to the unique immunosuppressive phenotype of measles. The mechanisms employed by MV-V inspire strategies to interfere with immunopathological TLR/MyD88 signaling.
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PMID:Measles virus V protein is a decoy substrate for IkappaB kinase alpha and prevents Toll-like receptor 7/9-mediated interferon induction. 1892 77

Neutrophils, historically known for their involvement in acute inflammation, are also targets for infection by many different DNA and RNA viruses. However, the mechanisms by which they recognize and respond to viral components are poorly understood. Polyinosinic:polycytidylic acid (poly(I:C)) is a synthetic mimetic of viral dsRNA that is known to interact either with endosomal TLR3 (not expressed by human neutrophils) or with cytoplasmic RNA helicases such as melanoma differentiation-associated gene 5 (MDA5) and retinoic acid-inducible gene I (RIG-I). In this study, we report that intracellularly administered poly(I:C) stimulates human neutrophils to specifically express elevated mRNA levels encoding type I IFNs, immunoregulatory cytokines, and chemokines, such as TNF-alpha, IL-12p40, CXCL10, CXCL8, CCL4, and CCL20, as well as classical IFN-responsive genes (IRG), including IFIT1 (IFN-induced protein with tetratricopeptide repeats 1)/IFN-stimulated gene (ISG)56, G1P2/ISG15, PKR (dsRNA-dependent protein kinase), and IFN-regulatory factor (IRF)7. Investigations into the mechanisms whereby transfected poly(I:C) promotes gene expression in neutrophils uncovered a crucial involvement of the MAPK-, PKR-, NF-kappaB-, and TANK (TNF receptor-associated NF-kappaB kinase)-binding kinase (TBK1)/IRF3-signaling transduction pathways, as illustrated by the use of specific pharmacological inhibitors. Consistent with the requirement of the cytoplasmic dsRNA pathway for antiviral signaling, human neutrophils were found to constitutively express significant levels of both MDA5 and RIG-I, but not TLR3. Accordingly, neutrophils isolated from MDA5-deficient mice had a partial impairment in the production of IFN-beta and TNF-alpha upon infection with encephalomyocarditis virus. Taken together, our data demonstrate that neutrophils are able to activate antiviral responses via helicase recognition, thus acting at the frontline of immunity against viruses.
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PMID:Activation of an immunoregulatory and antiviral gene expression program in poly(I:C)-transfected human neutrophils. 1894 Dec 47

Induction of Type I IFNs is a central event in antiviral responses and must be tightly controlled. The protein kinase TBK1 is critically involved in virus-triggered type I IFN signaling. In this study, we identify an alternatively spliced isoform of TBK1, termed TBK1s, which lacks exons 3-6. Upon Sendai virus (SeV) infection, TBK1s is induced in both human and mouse cells and binds to RIG-1, disrupting the interaction between RIG-I and VISA. Consistent with that result, overexpression of TBK1s inhibits IRF3 nuclear translocation and leads to a shutdown of SeV-triggered IFN-beta production. Taken together, our data indicate that TBK1s plays an inhibitory role in virus-triggered IFN-beta signaling pathways.
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PMID:Negative regulation of virus-triggered IFN-beta signaling pathway by alternative splicing of TBK1. 1897 54


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