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)

The transcription factor NF-kappaB is sequestered in the cytoplasm in a complex with IkappaB. Almost all NF-kappaB activation pathways converge on IkappaB kinase (IKK), which phosphorylates IkappaB resulting in Lys 48-linked polyubiquitination of IkappaB and its degradation. This allows migration of NF-kappaB to the nucleus where it regulates gene expression. IKK has two catalytic subunits, IKKalpha and IKKbeta, and a regulatory subunit, IKKgamma or NEMO. NEMO is essential for NF-kappaB activation, and NEMO dysfunction in humans is the cause of incontinentia pigmenti and hypohidrotic ectodermal dysplasia and immunodeficiency (HED-ID). The recruitment of IKK to occupied cytokine receptors, and its subsequent activation, are dependent on the attachment of Lys 63-linked polyubiquitin chains to signalling intermediates such as receptor-interacting protein (RIP). Here, we show that NEMO binds to Lys 63- but not Lys 48-linked polyubiquitin, and that single point mutations in NEMO that prevent binding to Lys 63-linked polyubiquitin also abrogates the binding of NEMO to RIP in tumour necrosis factor (TNF)-alpha-stimulated cells, the recruitment of IKK to TNF receptor (TNF-R) 1, and the activation of IKK and NF-kappaB. RIP is also destabilized in the absence of NEMO binding and undergoes proteasomal degradation in TNF-alpha-treated cells. These results provide a mechanism for NEMO's critical role in IKK activation, and a key to understanding the link between cytokine-receptor proximal signalling and IKK and NF-kappaB activation.
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PMID:Sensing of Lys 63-linked polyubiquitination by NEMO is a key event in NF-kappaB activation [corrected]. 1654 22

Anhidrotic ectodermal dysplasia with immunodeficiency is associated with multiple infections and a poor clinical outcome. Hypomorphic mutations in nuclear factor kappaB essential modulator (NEMO)/IkappaB kinase complex and a hypermorphic mutation in inhibitor alpha of nuclear factor kappaB (IkappaBalpha) both result in impaired nuclear factor kappaB activation and are associated with X-recessive and autosomal-dominant forms of anhidrotic ectodermal dysplasia with immunodeficiency, respectively. Autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency is also associated with a severe T-cell phenotype. It is not known whether hematopoietic stem cell transplantation can cure immune deficiency in children with anhidrotic ectodermal dysplasia with immunodeficiency. A boy with autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency and a severe T-cell immunodeficiency underwent transplantation at 1 year of age with haploidentical T-cell-depleted bone marrow after myeloablative conditioning. Engraftment occurred, with full hematopoietic chimerism. Seven years after transplantation, clinical outcome is favorable, with normal T-cell development. As expected, the developmental features of the anhidrotic ectodermal dysplasia syndrome have appeared and persisted. This is the first report of successful hematopoietic stem cell transplantation in a child with anhidrotic ectodermal dysplasia with immunodeficiency. Hematopoietic stem cell transplantation is well tolerated and efficiently cures the profound immunodeficiency associated with autosomal-dominant anhidrotic ectodermal dysplasia with immunodeficiency.
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PMID:Successful allogeneic hemopoietic stem cell transplantation in a child who had anhidrotic ectodermal dysplasia with immunodeficiency. 1676 98

The viral protein Nef is a virulence factor that plays multiple roles during the early and late phases of human immunodeficiency virus (HIV) replication. Nef regulates the cell surface expression of critical proteins (including down-regulation of CD4 and major histocompatibility complex class I), T-cell receptor signaling, and apoptosis, inducing proapoptotic effects in uninfected bystander cells and antiapoptotic effects in infected cells. It has been proposed that Nef intersects the CD40 ligand signaling pathway in macrophages, leading to modification in the pattern of secreted factors that appear able to recruit and activate T lymphocytes, rendering them susceptible to HIV infection. There is also increasing evidence that in vitro cell treatment with Nef induces signaling effects. Exogenous Nef treatment is able to induce apoptosis in uninfected T cells, maturation in dendritic cells, and suppression of CD40-dependent immunoglobulin class switching in B cells. Previously, we reported that Nef treatment of primary human monocyte-derived macrophages (MDMs) induces a cycloheximide-independent activation of NF-kappaB and the synthesis and secretion of a set of chemokines/cytokines that activate STAT1 and STAT3. Here, we show that Nef treatment is capable of hijacking cellular signaling pathways, inducing a very rapid regulatory response in MDMs that is characterized by the rapid and transient phosphorylation of the alpha and beta subunits of the IkappaB kinase complex and of JNK, ERK1/2, and p38 mitogen-activated protein kinase family members. In addition, we have observed the activation of interferon regulatory factor 3, leading to the synthesis of beta interferon mRNA and protein, which in turn induces STAT2 phosphorylation. All of these effects require Nef myristoylation.
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PMID:In vitro treatment of human monocytes/macrophages with myristoylated recombinant Nef of human immunodeficiency virus type 1 leads to the activation of mitogen-activated protein kinases, IkappaB kinases, and interferon regulatory factor 3 and to the release of beta interferon. 1718 89

Signaling via NF-kappaB is a key process during inflammation and thus constitutes an attractive target for anti-inflammatory therapeutic interventions. Especially during initial hyperinflammatory states of an acute illness such as sepsis or in the course of chronic inflammation and autoimmune diseases inhibition of IKK-driven NF-kappaB activation provides a promising treatment strategy. Given its critical role in innate and adaptive immune responses, however, there is a certain amount of risk due to induced immunodeficiency that may follow inhibitory treatment. Moreover, its primary anti-apoptotic function suggests that blockade of NF-kappaB activation has dramatic effects on cell functions and survival and eventually worsens the course of an inflammatory disease. An overview of canonical and alternative NF-kappaB activation and its critical role in immune responses will be provided. A main topic focuses on recent animal studies and data derived from genetic studies in humans that provide an insight into potential effects of different therapeutic modulations of NF-kappaB inflammatory signaling. The pros and cons of NF-kappaB inhibition and treatment strategies will be critically reviewed.
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PMID:Anti-inflammatory interventions of NF-kappaB signaling: potential applications and risks. 1807 Jun 16

Mutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), also called nuclear factor-kappaB (NF-kB) essential modulator (NEMO), gene are the most common single cause of incontinentia pigmenti (IP) in females and anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males. The IKBKG gene, located in the Xq28 chromosomal region, encodes for the regulatory subunit of the inhibitor of kappaB (IkB) kinase (IKK) complex required for the activation of the NF-kB pathway. Therefore, the remarkably heterogeneous and often severe clinical presentation reported in IP is due to the pleiotropic role of this signaling transcription pathway. A recurrent exon 4_10 genomic rearrangement in the IKBKG gene accounts for 60 to 80% of IP-causing mutations. Besides the IKBKG rearrangement found in IP females (which is lethal in males), a total of 69 different small mutations (missense, frameshift, nonsense, and splice-site mutations) have been reported, including 13 novel ones in this work. The updated distribution of all the IP- and EDA-ID-causing mutations along the IKBKG gene highlights a secondary hotspot mutation in exon 10, which contains only 11% of the protein. Furthermore, familial inheritance analysis revealed an unexpectedly high incidence of sporadic cases (>65%). The sum of the observations can aid both in determining the molecular basis of IP and EDA-ID allelic diseases, and in genetic counseling in affected families.
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PMID:Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations. 1835 May 53

Key to the pathogenicity of several viruses is activation of the canonical nuclear factor-kappaB (NF-kappaB) transcriptional pathway. Subversion of this tightly regulated mechanism is achieved through the production of host mimetic viral proteins that deregulate the transcription process. One such protein is ks-vFLIP (produced by the Kaposi's sarcoma herpes virus [KSHV]), which associates with IKKgamma, an essential component of the IKK complex or signalosome. This interaction renders the canonical NF-kappaB pathway constitutively active and has been linked to Kaposi's sarcoma and other malignancies. In order to elucidate the molecular basis underpinning ks-vFLIP-induced activation of the IKK signalosome, we have determined the crystal structure of a complex involving a fragment of IKKgamma bound to ks-vFLIP at 3.2 A. In addition to identifying and subsequently probing the ks-vFLIP-IKKgamma interface, we have also investigated the effects of a mutation implicated in the genetic disorder anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID).
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PMID:Crystal structure of a vFlip-IKKgamma complex: insights into viral activation of the IKK signalosome. 1853 60

Nuclear factor kappaB (NF-kappaB) is one of the critical transcription factors in inflammatory responses and replication of viruses such as human immunodeficiency virus (HIV). In fact, it has been demonstrated that various NF-kappaB inhibitors could block HIV replication. To explore more potent NF-kappaB inhibitors, we focused on carbocyclic adenine nucleosides that had been reported to have anti-inflammatory effects. We synthesized 15 carbocyclic adenine nucleoside compounds and examined their effects on the NF-kappaB-dependent gene expression using HEK293 cell line. Among these compounds, noraristeromycin (NAM) exhibited the most potent inhibitory effect on the NF-kappaB activity under the non-cytotoxic concentrations. NAM-inhibited IkappaBalpha phosphorylation and degradation upon stimulation of cells with tumour necrosis factor-alpha (TNF-alpha). In addition, NAM prevented p65 phoshorylation. These findings suggested that both IkappaB kinase-alpha (IKK-alpha) and -beta were targeted by NAM. Interestingly, in vitro kinase assay revealed that NAM inhibited the kinase activity of IKK-alpha more potently than that of IKK-beta. When we treated the cell lines, OM10.1 and Molt4/IIIB, in which HIV-1 is latently and chronically infected, we found a strong suppressive effect of NAM on HIV-1 viral replication upon stimulation with TNF-alpha.
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PMID:Inhibition of human immunodeficiency virus type 1 replication by blocking IkappaB kinase with noraristeromycin. 1871 98

The NADPH oxidase (NOX), an oligomeric enzyme, plays a key role in polymorphonuclear neutrophil (PMN)-mediated host defense by producing cytotoxic superoxide anion (O(2)( )). Whereas in vitro and biochemical studies have examined the assembly and activation of this important host immune defense system, few studies have examined the function of NOX in human patients with primary immunodeficiency other than chronic granulomatous disease. We studied the activation of NOX in PMN from patients with two distinct immunodeficiencies, IL-1R-associated kinase (IRAK)4 deficiency and NF-kappaB essential modulator (NEMO or IkappaB kinase gamma) deficiency. We observed impaired O(2)( ) generation by LPS-treated and fMLP-activated IRAK4-deficient PMN that correlated with decreased phosphorylation of p47(phox) and subnormal translocation of p47(phox), p67(phox), Rac2, and gp91(phox)/Nox2 to the membranes indicating that TLR4 signaling to the NOX activation pathway requires IRAK4. NEMO-deficient PMN generated significantly less O(2)( ) in response to LPS-primed fMLP and translocated less p67(phox) than normal PMN, although p47(phox) and Rac2 translocation were normal. Generally, responses of NEMO-deficient cells were intermediate between IRAK4-deficient cells and normal cells. Decreased LPS- and fMLP-induced phosphorylation of p38 MAPK in both IRAK4- and NEMO-deficient PMN implicates additional signal transduction pathways in regulating PMN activation by LPS and fMLP. Decreased activation of NOX may contribute to the increased risk of infection seen in patients with IRAK4 and NEMO deficiency.
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PMID:Impaired priming and activation of the neutrophil NADPH oxidase in patients with IRAK4 or NEMO deficiency. 1972 66

NEMO is an integral part of the IkappaB kinase complex and serves as a molecular switch by which the NF-kappaB signaling pathway can be regulated. Oligomerization and polyubiquitin (poly-Ub) binding, mediated through the regulatory CC2-LZ domain, were shown to be key features governing NEMO function, but the relationship between these two activities remains unclear. In this study, we solved the structure of this domain in complex with a designed ankyrin repeat protein, which helps its crystallization. We generated several NEMO mutants in this domain, including those associated with human diseases incontinentia pigmenti and immunodeficiency with or without anhidrotic ectodermal dysplasia. Analytical ultracentrifugation and thermal denaturation experiments were used to evaluate the dimerization properties of these mutants. A fluorescence-based assay was developed, as well, to quantify the interaction to monoubiquitin and poly-Ub chains. Moreover, the effect of these mutations was investigated for the full-length protein. We show that a proper folding of the ubiquitin-binding domain, termed NOA/UBAN/NUB, into a stable coiled-coil dimer is required but not sufficient for efficient interaction with poly-Ub. In addition, we show that binding to poly-Ub and, to a lesser extent, to monoubiquitin increases the stability of the NOA coiled-coil dimer. Collectively, these data provide structural insights into how several pathological mutations within and outside of the CC2-LZ's NOA ubiquitin binding site affect IkappaB kinase activation in the NF-kappaB signaling pathway.
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PMID:DARPin-assisted crystallography of the CC2-LZ domain of NEMO reveals a coupling between dimerization and ubiquitin binding. 1985 4

Viral infection triggers innate immune sensors to produce type I interferon. However, infection of T cells and macrophages with human immunodeficiency virus (HIV) does not trip those alarms. How HIV avoids activating nucleic acid sensors is unknown. Here we found that the cytosolic exonuclease TREX1 suppressed interferon triggered by HIV. In Trex1(-/-) mouse cells and human CD4(+) T cells and macrophages in which TREX1 was inhibited by RNA-mediated interference, cytosolic HIV DNA accumulated and HIV infection induced type I interferon that inhibited HIV replication and spreading. TREX1 bound to cytosolic HIV DNA and digested excess HIV DNA that would otherwise activate interferon expression via a pathway dependent on the kinase TBK1, the adaptor STING and the transcription factor IRF3. HIV-stimulated interferon production in cells deficient in TREX1 did not involve known nucleic acid sensors.
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PMID:The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. 2095 99


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