Alternative titles; symbols
HGNC Approved Gene Symbol: IKBKB
Cytogenetic location: 8p11.21 Genomic coordinates (GRCh38): 8:42,271,302-42,332,460 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p11.21 | Immunodeficiency 15A | 618204 | Autosomal dominant | 3 |
| Immunodeficiency 15B | 615592 | Autosomal recessive | 3 |
NFKB1 (164011) or NFKB2 (164012) is bound to REL (164910), RELA (164014), or RELB (604758) to form the NFKB complex. The NFKB complex is inhibited by I-kappa-B proteins (NFKBIA, 164008, or NFKBIB, 604495), which inactivate NF-kappa-B by trapping it in the cytoplasm. Phosphorylation of serine residues on the I-kappa-B proteins by kinases (IKBKA, 600664, or IKBKB) marks them for destruction via the ubiquitination pathway, thereby allowing activation of the NF-kappa-B complex. Activated NFKB complex translocates into the nucleus and binds DNA at kappa-B-binding motifs such as 5-prime GGGRNNYYCC 3-prime or 5-prime HGGARNYYCC 3-prime (where H is A, C, or T; R is an A or G purine; and Y is a C or T pyrimidine).
DiDonato et al. (1997) purified a cytokine-activated protein kinase complex, IKK (for I-kappa-B kinase), that phosphorylates I-kappa-B proteins on the sites that trigger their degradation. They molecularly cloned and identified a component of IKK, IKK-alpha (also known as IKBKA, IKK1, or IKKA), as a serine kinase. Zandi et al. (1997) identified a second subunit of the IKK complex, called IKK-beta. IKK-beta is 50% identical to IKK-alpha and contains the kinase domain, a leucine zipper, and a helix-loop-helix. Although either IKK-alpha and IKK-beta can homodimerize, they are usually found as heterodimers. Independently, Woronicz et al. (1997) identified IKK-beta. Mercurio et al. (1997) independently purified IKK-alpha and IKK-beta, which they termed IKK1 and IKK2, from HeLa cells.
Hu and Wang (1998) cloned and characterized IKKA and IKKB. Northern blot analysis revealed expression of major 3.6- and minor 7.0-kb IKKA transcripts in all tissues tested, with highest levels in heart, placenta, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, testis, and peripheral blood. IKKB was also ubiquitously expressed as major 3.4- and minor 6.5-kb transcripts. Expression of both transcripts was highest in 7-day mouse embryonic tissue. Hu and Wang (1998) suggested that IKKA and IKKB may be functionally related and cooperate in cells.
Woronicz et al. (1997) observed that IKK-beta activated NF-kappa-B when overexpressed and phosphorylated serine residues 32 and 36 of I-kappa-B-alpha and 19 and 23 of I-kappa-B-beta. The activity of IKK-beta was stimulated by TNF (191160) and IL1. IKK-alpha and IKK-beta formed heterodimers that interacted with NF-kappa-B-inducing kinase (NIK; 604655). Overexpression of catalytically inactive IKK-beta blocked cytokine-induced NF-kappa-B activation. Thus, the active I-kappa-B kinase complex appears to require 3 distinct protein kinases: IKK-alpha, IKK-beta, and NIK.
Mercurio et al. (1997) found that mutations in IKK2 had a more pronounced effect upon NFKB activation than did comparable mutations in IKK1.
Ozes et al. (1999) showed that AKT1 (164730) is involved in the activation of NFKB1 by TNF, following the activation of phosphatidylinositol 3-kinase (PIK3; see 171834). Constitutively active AKT1 induces NFKB1 activity, mediated by phosphorylation of IKK-alpha at threonine 23, which can be blocked by activated NIK. Conversely, NIK activation of NFKB1, mediated by phosphorylation of IKK-alpha at serine 176, is blocked by an AKT1 mutant lacking kinase activity (i.e., kinase-dead AKT), indicating that both AKT1 and NIK are necessary for TNF activation of NFKB1 through the phosphorylation of IKK-alpha. IKK-beta is not phosphorylated by either NIK or AKT1 and is apparently differentially regulated.
Yin et al. (1998) tested the activity of various antiinflammatory agents on the IKK complex. They demonstrated that aspirin and sodium salicylate specifically inhibit IKK-beta activity in vitro and in vivo by binding to IKK-beta to reduce ATP binding. Their results indicated that the antiinflammatory properties of aspirin and salicylate are mediated in part by their specific inhibition of IKK-beta, thereby preventing activation by NF-kappa-B of genes involved in the pathogenesis of the inflammatory response.
Delhase et al. (1999) demonstrated that in mammalian cells, phosphorylation of 2 sites at the activation loop of IKK-beta was essential for activation of IKK by TNF and IL1. Elimination of equivalent sites in IKK-alpha did not interfere with IKK activation. Thus IKK-beta, not IKK-alpha, is the target for proinflammatory stimuli. Once activated, IKK-beta autophosphorylated at a carboxy-terminal serine cluster. This phosphorylation decreased IKK activity and was suggested to prevent prolonged activation of the inflammatory response.
Tang et al. (2001) reported that IKK-beta is specifically proteolyzed by caspase-3 (600636)-related caspases at aspartic acid residues 78, 242, 373, and 546 during TNF-alpha-induced apoptosis. Proteolysis of IKK-beta eliminated its enzymatic activity, interfered with IKK activation, and promoted TNF-alpha killing. Point mutations that abrogated IKK-beta proteolysis generated a caspase-resistant IKK-beta mutant that suppressed TNF-alpha-induced apoptosis. This study demonstrated that TNF-alpha-induced apoptosis requires caspase-mediated proteolysis of IKK-beta.
Rossi et al. (2000) demonstrated a novel mechanism of antiinflammatory activity that was based on the direct inhibition and modification of the IKK-beta subunit of IKK. Since IKK-beta is responsible for the activation of NF-kappa-B by proinflammatory stimuli, Rossi et al. (2000) suggested that their findings explained how cyclopentenone prostaglandins function and can be used to improve the utility of COX2 (600262) inhibitors.
May et al. (2000) determined that an N-terminal alpha-helical region of NEMO (IKKG, or IKBKG; 300248) associates with a region of IKKA and IKKB that they termed the NBD for 'NEMO-binding domain.' The NBD is a 6-amino acid C-terminal segment within the region denoted alpha-2 of IKKA and IKKB. Wildtype, but not mutant, NDB peptide inhibited cytokine-induced NFKB activation and ameliorated experimental acute inflammation.
Hu et al. (2004) investigated the pathologic relationship between phosphorylated AKT, or AKT-p, and FOXO3A (602681) in primary tumors. FOXO3A was excluded from the nuclei of some tumors lacking AKT-p, suggesting an AKT-independent mechanism of regulating FOXO3A localization. Hu et al. (2004) provided evidence for such a mechanism by showing that IKK physically interacted with, phosphorylated, and inhibited FOXO3A independent of AKT and caused proteolysis of FOXO3A via the ubiquitin (see 191339)-dependent proteasome pathway. Cytoplasmic FOXO3A correlated with expression of IKKB or AKT-p in many tumors and was associated with poor survival in breast cancer. Constitutive expression of IKKB promoted cell proliferation and tumorigenesis that could be overridden by FOXO3A. These results suggested that the negative regulation of FOXO factors by IKK is a key mechanism for promoting cell growth and tumorigenesis.
Using mouse embryo fibroblasts lacking both Ikbkb and Ikbka, Sizemore et al. (2004) found that both proteins were required for induction of a subset of Ifng (147570)-stimulated genes independent of Nfkb activation and with no defect in Stat1 (600555) activation or function. Sizemore et al. (2004) concluded that the IKK-dependent pathway is an additional important pathway for IFNG-stimulated gene expression.
Wu et al. (2006) demonstrated that NEMO, the regulatory subunit of the IKK complex, associates with activated ATM (607585) after the induction of DNA double-strand breaks. ATM is exported in a NEMO-dependent manner to the cytoplasm, where it associates with and causes the activation of IKK in a manner dependent on another IKK regulator, a protein rich in glutamate, leucine, lysine, and serine (ELKS; 607127). Thus, Wu et al. (2006) concluded that regulated nuclear shuttling of NEMO links 2 signaling kinases, ATM and IKK, to activate NF-kappa-B by genotoxic signals.
Using biochemical and genetic approaches, Wegener et al. (2006) demonstrated that IKKB is critical for regulation of the CARMA1 (CARD11; 607210)-BCL10 (603517)-MALT1 (604860) (CBM) complex. They found that IKKB is required not only for initial complex formation, but also for triggering disengagement of BCL10 and MALT1 by phosphorylation of the C terminus of BCL10, thereby negatively influencing T-cell receptor signaling. Wegener et al. (2006) proposed a model in which IKKB is associated with BCL10-MALT1 in resting T cells. Following T-cell activation, protein kinase C-theta (PRKCQ; 600448) phosphorylates CARMA1 and induces association of CARMA1 with BCL10-MALT1. Formation of the BCM complex induces maximal activation of IKK through activation of IKKG. IKKB phosphorylates BCL10 in its MALT1 interaction domain, causing BCL10 and MALT1 to disassociate, resulting in attenuation of NFKB signaling and cytokine production.
Mittal et al. (2006) found that the Yersinia YopJ virulence factor inhibited the host inflammatory response and induced apoptosis of immune cells by catalyzing acetylation of 2 ser residues in the activation loop of MEK2 (MAP2K2; 601263), thereby blocking MEK2 activation and signal propagation. YopJ also caused acetylation of a thr residue in the activation loop of both IKKA and IKKB. Mittal et al. (2006) concluded that ser/thr acetylation is a mode of action for bacterial toxins that may also occur under nonpathogenic conditions to regulate protein function.
Zaph et al. (2007) showed that intestinal epithelial cell (IEC)-intrinsic IKKB-dependent gene expression is a critical regulator of responses of dendritic cells and CD4+ (186940) T cells in the gastrointestinal tract. Mice with an IEC-specific deletion of IKKB showed reduced expression of the epithelial cell-restricted cytokine thymic stromal lymphopoietin (607003) in the intestine and, after infection with the gut-dwelling parasite Trichuris, failed to develop a pathogen-specific CD4+ T helper type-2 (Th2) response and were unable to eradicate infection. Furthermore, these animals showed exacerbated production of dendritic cell-derived interleukin-12/23p40 (161561) and TNFA (191160), had increased levels of CD4+ T cell-derived interferon-gamma (147570) and interleukin-17 (603149), and developed severe intestinal inflammation. Blockade of proinflammatory cytokines during Trichuris infection ablates the requirement for IKKB in IECs to promote CD4+ Th2 cell-dependent immunity, identifying an essential function for IECs in tissue-specific conditioning of dendritic cells and limiting type 1 cytokine production in the gastrointestinal tract. Zaph et al. (2007) concluded that the balance of IKKB-dependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis by promoting mucosal immunity and limiting chronic inflammation.
Using mouse lacking Ikkb in different cell types, Rius et al. (2008) showed that NF-kappa-B was a critical transcriptional activator of Hif1a (603348) and that basal NF-kappa-B activity was required for Hif1a protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals. Ikkb deficiency resulted in defective induction of Hif1a target genes including vascular endothelial growth factor (VEGF; 192240). Ikkb was essential for Hif1a accumulation in macrophages experiencing a bacterial infection. Rius et al. (2008) concluded that IKKB is an important physiologic contributor to the hypoxic response, linking it to innate immunity and inflammation.
Zhang et al. (2013) showed that the hypothalamus is important for the development of whole-body aging in mice, and that the underlying basis involves hypothalamic immunity mediated by IKK-beta, NF-kappa-B, and related microglia-neuron immune crosstalk. Several interventional models were developed showing that aging retardation and life span extension were achieved in mice by preventing aging-related hypothalamic or brain IKK-beta and NF-kappa-B activation. Mechanistic studies further revealed that IKK-beta and NF-kappa B inhibit gonadotropin-releasing hormone (GNRH; 152760) to mediate aging-related hypothalamic GNRH decline, and GNRH treatment amends aging-impaired neurogenesis and decelerates aging. Zhang et al. (2013) concluded that the hypothalamus plays a programmatic role in aging development via immune-neuroendocrine integration.
Shinohara et al. (2014) showed that the CARMA1 (607210)-TAK1 (MAP3K7; 602614)-IKBKB module is a switch mechanism for NFKB activation in B-cell receptor signaling. Experimental and mathematical modeling analyses showed that IKK activity is regulated by positive feedback from IKBKB to TAK1, generating a steep dose response to B-cell receptor stimulation. Mutation of the scaffolding protein CARMA1 at ser578, an IKBKB target, not only abrogated late TAK1 activity but also abrogated the switchlike activation of NFKB in single cells, suggesting that phosphorylation of this residue accounts for the feedback.
Using reporter assays and knockdown studies in human cells, Wu et al. (2016) showed that LRRC14 (619368) was a potent inhibitor of NFKB signaling. Further analysis revealed that LRRC14 inhibited NFKB activation at the level of the IKK complex. Coimmunoprecipitation and mutation analyses showed that LRRC14 bound the helix-loop-helix domain of IKBKB and blocked its interaction with NEMO, thereby inhibiting IKBKB phosphorylation and NFKB activation.
Shindo et al. (1998) mapped the IKBKB gene to chromosome 8p12-p11 by FISH. By FISH and radiation hybrid analysis, Ambros et al. (1998) mapped the IKBKB gene to 8p11.2.
Crystal Structure
Xu et al. (2011) reported the crystal structure of IKK-beta in complex with an inhibitor at a resolution of 3.6 angstroms. The structure revealed a trimodular architecture comprising the kinase domain, a ubiquitin-like domain (ULD), and an elongated, alpha-helical scaffold/dimerization domain (SDD). Unexpectedly, the predicted leucine zipper and helix-loop-helix motifs do not form these structures but are part of the SDD. The ULD and SDD mediate a critical interaction with I-kappa-B-alpha that restricts substrate specificity, and the ULD is also required for catalytic activity. The SDD mediates IKK-beta dimerization, but dimerization per se is not important for maintaining IKK-beta activity and instead is required for its activation.
Immunodeficiency 15B
In 4 patients of Cree ancestry from Canada with primary immunodeficiency (IMD15B; 615592), Pannicke et al. (2013) identified a homozygous truncating mutation in the IKBKB gene (c.1292dupG; 603258.0001), resulting in complete loss of protein function. The mutation was found by homozygosity mapping followed by sequencing of genes in the candidate region. The patients presented in infancy with life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies showed hypo- or agammaglobulinemia with relatively normal numbers of circulating B and T cells. Functional and gene expression studies of patient fibroblasts showed variable effects on receptor activation and NFKB signaling involved in immunity. There was impaired phosphorylation of NFKBIA (164008) in response to stimulation with TNFA (191160) and flagellin, which acts through TLR5 (603031), but only a marginally impaired response to IL1B (147720). IL6 (147620) response to TNFA was normal, but it was reduced in response to lipopolysaccharide, with acts through TLR4 (603030). These studies showed selective dependence of the regulation of NFKB target genes on IKBKB function. Patient peripheral blood B and T cells were almost exclusively of the naive type, and B, T, and NK cells showed poor differentiation or mitogenic responses under certain conditions. These findings were consistent with the role of IKBKB in transmitting signals by various surface receptors.
In a Turkish infant, born of consanguineous parents, with fatal IMD15B, Nielsen et al. (2014) identified a homozygous truncating mutation in the IKBKB gene (R272X; 603258.0002). The mutation was found by whole-exome sequencing. Western blot analysis of patient cells showed a complete lack of the IKBKB protein, although IKKA (CHUK; 600664) and NEMO (IKBKG; 300248) levels were similar to control. Stimulation of patient T cells failed to result in phosphorylation of p65 (NFKB3; 164014), and patient T cells failed to proliferate in response to stimulation. The findings indicated that IKBKB is critical for activation of T cells and differentiation of B cells.
Immunodeficiency 15A
In probands from 2 unrelated families with an immune deficiency with combined T and B cell deficiency as well as immune activation of both CD4+ and CD8+ T cells (IMD15A; 618204), Cardinez et al. (2018) identified the same de novo missense mutation in the IKBKB gene (V203I; 603258.0003). This mutation changes the highly conserved valine at position 203, which is conserved to at least Drosophila melanogaster and is located within the active site of IKK2 on the second lobe of the kinase domain, which phosphorylates the N-terminal region of IKB-alpha (NFKBIA; 164008) and leads to activation of NF-kappa-B (see 164011). The mutant protein was predicted to assume an unstable conformation, while maintaining its kinase activity, but disrupting the tetrameric interaction of IKK2.
Li et al. (1999) disrupted the IKK2 gene in mice. Ikk2 -/- mice died between embryonic day 12.5 and 14. Death was due to extensive liver damage from apoptosis, but these mice could be rescued by inactivation of the TNFR1 (191190) gene. Mouse embryonic fibroblast cells isolated from Ikk2 -/- embryos showed a marked reduction in TNF-alpha and IL1-alpha-induced NFKB activity and enhanced apoptosis in response to TNF-alpha. IKK1 associated with IKK-gamma (NEMO), another component of the IKK complex.
Yuan et al. (2001) demonstrated that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of IKKB attenuated insulin signaling in cultured cells, whereas inhibition of IKKB reversed insulin resistance. Thus, Yuan et al. (2001) concluded that IKKB, rather than the cyclooxygenases (see 600262), appears to be the relevant molecular target. Heterozygous deletion (IKKB +/-) protected against the development of insulin resistance during high-fat feeding and in obese Lep (ob/ob) (see 164160) mice. Yuan et al. (2001) concluded that their findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus (125853) and identified the IKKB pathway as a target for insulin sensitization.
Pasparakis et al. (2002) used Cre/loxP-mediated gene targeting to investigate the function of IKK2 specifically in epidermal keratinocytes. IKK2 deficiency inhibits NFKB activation, but does not lead to cell-autonomous hyperproliferation or impaired differentiation of keratinocytes. Mice with epidermis-specific deletion of IKK2 develop a severe inflammatory skin disease, which is caused by a tumor necrosis factor (191160)-mediated, alpha-beta T-cell-independent inflammatory response that develops in the skin shortly after birth. Pasparakis et al. (2002) concluded that the critical function of IKK2-mediated NFKB activity in epidermal keratinocytes is to regulate mechanisms that maintain the immune homeostasis of the skin.
Egan et al. (2004) used mice with selective ablation of Nfkb signaling through Ikkb in intestinal epithelial cells to show that this results in a significant increase in radiation-induced epithelial cell apoptosis. Bacterial lipopolysaccharide, which is normally a radioprotective agent, was radiosensitizing in the Ikkb-deficient intestinal epithelial cells. Egan et al. (2004) concluded that IKKB is a key target for radioprotection in the intestine.
Using a mouse model of colitis-associated cancer, Greten et al. (2004) showed that deletion of Ikk-beta in intestinal epithelial cells did not decrease inflammation, but it led to a dramatic decrease in tumor incidence without affecting tumor size. This decrease in tumor incidence was linked to increased epithelial apoptosis during tumor promotion. In contrast, deletion of Ikk-beta in myeloid cells resulted in a significant decrease in tumor size. This deletion diminished expression of proinflammatory cytokines, which may serve as tumor growth factors, without affecting apoptosis. Thus, specific inactivation of the Ikk-beta/Nfkb pathway in 2 different cell types attenuated formation of inflammation-associated tumors. Greten et al. (2004) suggested that, in addition to suppressing apoptosis in advanced tumors, IKK-beta may link inflammation to cancer.
Cai et al. (2004) created transgenic mice with Nfkb either activated or inhibited selectively in skeletal muscle through expression of constitutively active IKKB or a dominant inhibitory form of IKBA (164008), respectively. They referred to these mice as MIKK (muscle-specific expression of IKKB) or MISR (muscle-specific expression of IKBA superrepressor), respectively. MIKK mice showed profound muscle wasting that resembled clinical cachexia, whereas MISR mice showed no overt phenotype. Muscle loss in MIKK mice was due to accelerated protein breakdown through ubiquitin-dependent proteolysis. Expression of the E3 ligase Murf1 (RNF28; 606131), a mediator of muscle atrophy, was increased in MIKK mice. Pharmacologic or genetic inhibition of the Ikkb/Nfkb/Murf1 pathway in MIKK mice reversed the muscle atrophy. The Nfkb inhibition in MISR mice substantially reduced denervation- and tumor-induced muscle loss and improved survival rates. The results were consistent with a critical role for NFKB in the pathology of muscle wasting and established NFKB as an important clinical target for the treatment of muscle atrophy.
In mouse livers, Cai et al. (2005) demonstrated that Nfkb and transcriptional targets were activated by obesity and high-fat diet. They generated transgenic mice with a similar state of chronic, subacute inflammation due to low-level constitutive activation of Ikbkb in the liver; these mice exhibited a type II diabetes phenotype characterized by hyperglycemia, profound hepatic insulin resistance, and moderate systemic insulin resistance, including effects in muscle. Hepatic production of proinflammatory cytokines in these mice was increased to an extent similar to that induced by a high-fat diet in wildtype mice, and parallel increases were observed in cytokine signaling in liver and muscle. Insulin resistance was improved by systemic neutralization of Il6 (147620) or salicylate inhibition of Ikbkb. Cai et al. (2005) concluded that lipid accumulation in the liver leads to subacute hepatic inflammation through NFKB activation and downstream cytokine production, causing both local and systemic insulin resistance.
Arkan et al. (2005) generated mice lacking Ikbkb in hepatocytes or myeloid cells and observed that mice with hepatic conditional knockout of Ikbkb retained liver insulin responsiveness but developed insulin resistance in muscle and fat in response to a high-fat diet, obesity, or aging. In contrast, mice with myeloid cell conditional knockout of Ikbkb retained global insulin sensitivity and were protected from insulin resistance. Arkan et al. (2005) concluded that IKBKB acts locally in liver and systemically in myeloid cells, where NFKB activation induces inflammatory mediators that cause insulin resistance. The authors stated that this was the first direct genetic evidence for a major role of myeloid cells in control of global insulin sensitivity.
Mourkioti et al. (2006) inactivated Ikk2 specifically in mouse muscle cells to deplete Nfkb signaling. These muscles showed increased strength, maintained normal physiology, blocked protein degradation under atrophy conditions, and displayed enhanced muscle regeneration in response to injury. Abrogation of Nfkb signaling provided even better protection against muscle atrophy when combined with a muscle-specific transgene expressing Igf1 (147440). Mourkioti et al. (2006) proposed that control of inflammatory pathways may be important in the treatment of muscle atrophy and degeneration.
Baumann et al. (2007) generated transgenic mice allowing acinar cell-specific suppression and conditional activation of Ikk activity in the pancreas. Expression of dominant-negative Ikk2 ameliorated cerulein-induced pancreatitis without affecting activation of trypsin. Expression of constitutively active Ikk2 was sufficient to induce acute pancreatitis with an acinar cell-specific phenotype that included edema, cellular infiltrates, necrosis, and elevation of serum lipase levels, as well as pancreatic fibrosis. Ikk2 activation caused increased expression of known Nfkb target genes; increased expression of Tnf-alpha was found to be critical for the onset of Ikk2-induced pancreatitis. Baumann et al. (2007) concluded that the IKK2-NFKB pathway is key to the development of experimental pancreatitis and is the major factor in the typical inflammatory response of the disease.
Greten et al. (2007) found that mice lacking Ikkb in myeloid cells were more susceptible to endotoxin-induced mortality than control mice. Mutant mice showed increased levels of Il1b (147720) following endotoxin challenge or bacterial infection due to enhanced pro-Il1b processing. Prolonged pharmacologic inhibition of Ikkb, which interferes with NF-kappa-B activation in the whole animal, also increased lipopolysaccharide-induced mortality and plasma Il1b. Greten et al. (2007) concluded that IKKB-dependent NF-kappa-B activation has a role in reducing IL1B secretion.
The atypical fungal pathogen Pneumocystis is a serious and sometimes fatal pathogen in immunocompromised, but not healthy, humans who lack a protective CD4-positive T-cell response. Pneumocystis attaches to lung epithelial cells (LECs), triggering an NFKB response. Perez-Nazario et al. (2013) generated mice lacking Ikk2 specifically in LECs and found that they had a delayed onset of Th17 and B-cell responses in lung, as well as delayed fungal clearance. The delayed clearance was associated with an exacerbated late immune response, impaired pulmonary function, and altered lung histology. Perez-Nazario et al. (2013) concluded that IKK2-dependent LEC responses modulate the pulmonary immune response to respiratory fungal infection.
In 4 patients of Cree ancestry from Canada with a primary immunodeficiency (IMD15B; 615592), Pannicke et al. (2013) identified a homozygous 1-bp duplication (c.1292dupG) in exon 13 of the IKBKB gene, resulting in a frameshift and premature termination (Gln432ProfsTer62) and the loss of most of the alpha-helical scaffold dimerization domain. The mutation was found by homozygosity mapping followed by sequencing of genes in the candidate region. The mutation was not found in the dbSNP or 1000 Genomes Project databases, and segregated with the disorder in the families. IKBKB mRNA was decreased in patient cells, likely reflecting nonsense-mediated mRNA decay. Western blot analysis of patient cells showed complete lack of the IKBKB protein, consistent with a loss of function. Patient cells also showed decreased protein levels of IKK1 (600664), IKBKG (300248), and p65 (NFKB3; 164014) compared to control cells. Functional and gene expression studies of patient fibroblasts showed variable effects on receptor activation and NFKB signaling involved in immunity. There was impaired phosphorylation of NFKBIA (164008) in response to stimulation with TNF-alpha (191160) and flagellin, which acts through TLR5 (603031), but only a marginally impaired response to IL1B (147720). IL6 (147620) response to TNFA was normal, but it was reduced in response to lipopolysaccharide, with acts through TLR4 (603030). These studies showed selective dependence of the regulation of NFKB target genes on IKBKB function. Patient peripheral blood B and T cells were almost exclusively of the naive type, and B, T, and NK cells showed poor differentiation or mitogenic responses under certain conditions. These findings were consistent with the role of IKBKB in transmitting signals by various surface receptors. Pannicke et al. (2013) noted that the phenotype in these patients with null mutations in IKBKB is not as severe as that in the null mouse model, which is lethal (Li et al., 1999).
In a Turkish infant, born of consanguineous parents, with fatal immunodeficiency (IMD15B; 615592), Nielsen et al. (2014) identified a homozygous c.814C-T transition in the IKBKB gene, resulting in an arg272-to-ter (R272X) substitution. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. It segregated with the disorder in the family and was filtered against common variant databases. The patient died of systemic infection by Mycobacterium bovis 11 months after BCG vaccination. Immunologic workup showed increased serum IgM, absence of isotype-switched memory B cells, and low numbers of D45R0+ memory T cells. The findings indicated that IKBKB is critical for activation of T cells and differentiation of B cells.
In probands from 2 unrelated families with immunodeficiency 15A (IMD15A; 618204), Cardinez et al. (2018) identified a heterozygous G-to-A transition at nucleotide 607 (c.607G-A, GRCh37) of the IKBKB gene, resulting in a valine-to-isoleucine substitution at codon 203 (V203I). This mutation occurred de novo in both probands. The mutation was also present in the 2 affected children of 1 proband. The mutant protein was predicted to assume an unstable conformation which would disrupt the tetrameric interaction of IKK2, while retaining its kinase activity. The V203I mutation was not reported in gnomAD, ExAC, or dbSNP.
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Arkan, M. C., Hevener, A. L., Greten, F. R., Maeda, S., Li, Z.-W., Long, J. M., Wynshaw-Boris, A., Poli, G., Olefsky, J., Karin, M. IKK-beta links inflammation to obesity-induced insulin resistance. Nature Med. 11: 191-198, 2005. [PubMed: 15685170] [Full Text: https://doi.org/10.1038/nm1185]
Baumann, B., Wagner, M., Aleksic, T., von Wichert, G., Weber, C. K., Adler, G., Wirth, T. Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo. J. Clin. Invest. 117: 1502-1513, 2007. [PubMed: 17525799] [Full Text: https://doi.org/10.1172/JCI30876]
Cai, D., Frantz, J. D., Tawa, N. E., Jr., Melendez, P. A., Oh, B.-C., Lidov, H. G. W., Hasselgren, P.-O., Frontera, W. R., Lee, J., Glass, D. J., Shoelson, S. E. IKK-beta/NF-kappa-B activation causes severe muscle wasting in mice. Cell 119: 285-298, 2004. [PubMed: 15479644] [Full Text: https://doi.org/10.1016/j.cell.2004.09.027]
Cai, D., Yuan, M., Frantz, D. F., Melendez, P. A., Hansen, L., Lee, J., Shoelson, S. E. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappa-B. Nature Med. 11: 183-190, 2005. [PubMed: 15685173] [Full Text: https://doi.org/10.1038/nm1166]
Cardinez, C., Miraghazadeh, B., Tanita, K., da Silva, E., Hoshino, A., Okada, S., Chand, R., Asano, T., Tsumura, M., Yoshida, K., Ohnishi, H., Kato, Z., and 12 others. Gain-of-function IKBKB mutation causes human combined immune deficiency. J. Exp. Med. 215: 2715-2724, 2018. [PubMed: 30337470] [Full Text: https://doi.org/10.1084/jem.20180639]
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