Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: RELA
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38) : 11:65,653,601-65,663,857 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.1 | Autoinflammatory disease, familial, Behcet-like-3 | 618287 | Autosomal dominant | 3 |
NFKB1 (164011) or NFKB2 (164012) is bound to REL (164910), RELA, or RELB (604758) to form the NFKB complex. The p50 (NFKB1)/p65 (RELA) heterodimer is the most abundant form of NFKB. The NFKB complex is inhibited by I-kappa-B proteins (NFKBIA, 164008 or NFKBIB, 604495), which inactivate NFKB by trapping it in the cytoplasm. Phosphorylation of serine residues on the I-kappa-B proteins by kinases (IKBKA, 600664, or IKBKB, 603258) marks them for destruction via the ubiquitination pathway, thereby allowing activation of the NFKB 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).
Zhong et al. (1998) reported that the transcriptional activity of NF-kappa-B is stimulated upon phosphorylation of its p65 subunit on serine-276 by protein kinase A (PKA). The transcriptional coactivator CBP (600140)/p300 (602700) associates with NF-kappa-B p65 through 2 sites, an N-terminal domain that interacts with the C-terminal region of unphosphorylated p65, and a second domain that only interacts with p65 phosphorylated on serine-276. Phosphorylation by PKA both weakens the interaction between the N- and C-terminal regions of p65 and creates an additional site for interaction with CBP/p300. Therefore, PKA regulates the transcriptional activity of NF-kappa-B by modulating its interaction with CBP/p300.
Jacobs and Harrison (1998) and Huxford et al. (1998) determined the structure of the NFKBIA ankyrin repeat domain, bound to a partially truncated NFKB heterodimer (p50/p65), by x-ray crystallography at 2.7- and 2.3-angstrom resolution, respectively. It shows a stack of 6 NFKBIA ankyrin repeats facing the C-terminal domains of the NFKB rel homology regions. Contacts occur in discontinuous patches, suggesting a combinatorial quality for ankyrin repeat specificity. The first 2 repeats cover an alpha helically ordered segment containing the p65 nuclear localization signal. The position of the sixth ankyrin repeat shows that full-length NFKBIA will occlude the NFKB DNA-binding cleft. The orientation of NFKBIA in the complex places its N- and C-terminal regions in appropriate locations for their known regulatory functions. Baeuerle (1998) discussed the model of interactions between NFKBIA and NFKB.
Chen et al. (2001) noted that the events involved in the release of NFKB from IKBA are relatively well understood, but the regulation of nuclear forms of NFKB that ensure transient transcriptional responses are less well delineated. Luciferase reporter analysis showed that treatment with trichostatin A (TSA), an inhibitor of multiple histone deacetylases (e.g., HDAC1; 601241), results in prolonged intranuclear expression of RELA after TNFA (191160) stimulation. Expression of HDAC3 (605166), but not other HDACs, was found to inhibit kappa-B luciferase activity and abolish the acetylation of RELA, which is mediated by p300 or CBP but not PCAF (602303), in the absence of TSA. Coimmunoprecipitation and mammalian 2-hybrid analyses indicated that RELA and HDAC3 associate through their N termini. Fluorescence microscopy demonstrated that coexpression of RELA with HDAC3, but not with HDAC1, results in cytoplasmic instead of nuclear localization of RELA, and this is dependent on the expression of exportin-1 (XPO1; 602559). Coexpression of HDAC3 in the presence of p300 allowed binding of RELA to IKBA, suggesting that deacetylation of RELA stimulates IKBA binding and the termination of the NFKB transcriptional response. Fluorescence microscopy showed that in the presence of HDAC3, RELA expression shifts to the cytoplasm in wildtype murine embryo fibroblasts but not in fibroblasts obtained from Ikba -/- mice, indicating that IKBA is required for the nuclear export of deacetylated RELA. Chen et al. (2001) concluded that RELA is a nonhistone substrate of HDAC3 and that IKBA-dependent nuclear export of the HDAC3-deacetylated RELA replenishes the depleted cytoplasmic pool of latent NFKB-IKBA complexes for subsequent NFKB responses.
Zhong et al. (2002) demonstrated that transcriptionally inactive nuclear NFKB in resting cells consists of homodimers of either p65 or p50 complexed with the histone deacetylase HDAC1. Only the p50-HDAC1 complexes bound to DNA and suppressed NFKB-dependent gene expression in unstimulated cells. Appropriate stimulation caused nuclear localization of NFKB complexes containing phosphorylated p65 that associated with CBP and displaced the p50-HDAC1 complexes. These results demonstrated that phosphorylation of p65 determines whether it associates with either CBP or HDAC1, ensuring that only p65 entering the nucleus from cytoplasmic NFKB-IKB complexes can activate transcription.
Because therapeutics inhibiting RAS and NFKB pathways are used to treat human cancer, experiments assessing the effects of altering these regulators have been performed in mice. The medical relevance of murine studies is limited, however, by differences between mouse and human skin, and by the greater ease of transforming murine cells. To study RAS and NFKB in a setting more relevant to human tumorigenesis, Dajee et al. (2003) expressed the active HRAS gly12-to-val mutation (190020.0001), NFKB p65, and a stable NFKB repressor mutant of IKBA (164008) in human skin tissue. Although implicated in promoting features of neoplasia in other settings, coexpression of oncogenic RAS with NFKB subunits failed to support proliferation. Coexpression of RAS and IKBA produced large neoplasms with deep invasion through fat into underlying muscle and fascia, similar to human squamous cell carcinomas (SCC), in 3 weeks. Dajee et al. (2003) demonstrated that growth arrest triggered by oncogenic RAS can be bypassed by IKBA-mediated blockade of NFKB and that RAS opposed the increased susceptibility to apoptosis caused by NFKB blockade, generating malignant human epidermal tissue resembling SCC.
Smahi et al. (2002) reviewed the NFKB signaling pathway, with emphasis on its dysregulation in the genetic disorders incontinentia pigmenti (308300), hypohidrotic/anhidrotic ectodermal dysplasia (see 305100), anhidrotic ectodermal dysplasia with immunodeficiency (EDAID; 300291), and EDA-ID with osteopetrosis and lymphoedema (see 300291).
In rat sciatic nerves, Nickols et al. (2003) found that expression of the activated p65 subunit of NFKB was high in the nuclei of premyelinating Schwann cells and then progressively declined until it was nearly absent in adults. NFKB expression preceded and was necessary for the upregulation of the transcription factor Oct6 (POU3F1; 602479), which has been shown to play a role in the differentiation of promyelin cells to myelinating cells. The authors concluded that NFKB is upstream of Oct6 induction and is also required for the formation of peripheral myelin.
Using yeast 2-hybrid, protein pull-down, coimmunoprecipitation, and mutation analyses, Asamitsu et al. (2003) found that the C-terminal region of AO7 (RNF25; 616014) interacted directly with the C-terminal half of NF-kappa-B p65. In transfected HEK293 cells, the AO7-p65 interaction was enhanced by TNF or IL1-beta (IL1B; 147720) stimulation, which causes nuclear translocation of NF-kappa-B and phosphorylation of p65. A ubiquitination-competent RING finger domain of AO7 was necessary for NF-kappa-B transcriptional activation. Asamitsu et al. (2003) concluded that AO7 modulates p65 transcriptional activity.
Using cDNA microarray and in vitro analyses, Kelly et al. (2004) found that the commensal bacterium Bacteroides thetaiotaomicron attenuated inflammatory responses, notably IL8 (146930) production, in intestinal cell lines exposed to pathogenic Salmonella enteritidis and a number of other inflammatory mediators. The commensal organism induced CRM1 (XPO1)-independent nuclear export, rather than import only, of the NFKB subunit RELA, with an eventual predominance of RELA cytoplasmic distribution after the peak of RELA induction by IL1A (147760) and IL1B. RELA nucleocytoplasmic redistribution coincided with export of PPARG (601487), and immunoprecipitation analysis indicated that PPARG-RELA association was dependent on the PPARG C-terminal ligand-binding domain. Kelly et al. (2004) concluded that at least some commensal bacteria contribute to immune homeostasis through an antiinflammatory mechanism involving PPARG and NFKB.
Mazzeo et al. (2004) found positive immunostaining for activated p65 NFKB in nerve biopsies from 5 patients with chronic inflammatory demyelinating polyneuropathy (CIDP; see 139393), 5 with familial amyloidotic polyneuropathy (FAP; see 176300), and 3 with vasculitis. Mild to moderate staining was detected in 2 to 15% of epineurial and endoneurial vessel walls, 5 to 10% of outer layers of myelin sheaths, and in amyloid deposits of FAP. There was an association between NFKB staining and localization of the terminal membrane attack complex (MAC) of the complement system. No staining was seen in 3 control specimens. Mazzeo et al. (2004) suggested a role for NFKB in inflammatory conditions of the peripheral nervous system.
Signaling by the transcription factor NFKB involves its release from IKB in the cytosol, followed by translocation into the nucleus. NFKB regulation of I-kappa-B-alpha transcription represents a delayed negative feedback loop that drives oscillations in NFKB translocation. Nelson et al. (2004) reported that single-cell time-lapse imaging and computational modeling of NFKB localization showed asynchronous oscillations following cell stimulation that decreased in frequency with increased I-kappa-B-alpha transcription. Transcription of target genes depended on oscillation persistence, involving cycles of NFKB phosphorylation and dephosphorylation. Nelson et al. (2004) concluded that the functional consequences of NFKB signaling may thus depend on number, period, and amplitude of oscillations.
Barken et al. (2005) commented on the paper by Nelson et al. (2004), suggesting that altering expression levels of fluorescently-tagged signal proteins can severely affect the dynamic behavior of the signaling pathway under study and cautioning against equating the signaling behavior of genetically engineered cells with that of normal cells. In response to the comment by Barken et al. (2005), Nelson et al. (2005) stated that their experimental data showed no correlation between NF-kappa-B (RelA) expression level and oscillation dynamics. Nelson et al. (2005) showed that a small change to the computational model used by Barken et al. (2005) to generate their theoretical data reduced the apparent discrepancies. Cell system differences and possible compensatory changes to normal signaling in their genetically knockout cells may explain differences between the 2 studies.
Liu et al. (2006) showed that preexisting nuclear RELA positively regulates ultraviolet (UV) irradiation-induced activation of JNK (MAPK8; 601158). In UV-irradiated mouse fibroblasts, they found that Pkc-delta (176977) was required for Rela to activate Jnk, thereby contributing to UV-induced apoptosis.
By genomewide mapping of RELA-bound loci in lipopolysaccharide (LPS)-stimulated monocytes, together with global gene expression profiling, Lim et al. (2007) identified an overrepresentation of the E2F1 (189971)-binding motif among RELA-bound loci associated with NFKB target genes. Knockdown of endogenous E2F1 impaired the LPS inducibility of the proinflammatory cytokines CCL3 (182283), IL23A (605580), TNF, and IL1B. Sequential chromatin immunoprecipitation and coimmunoprecipitation analysis showed that E2F1 existed as a complex with p50/RELA in LPS-stimulated monocytes. Lim et al. (2007) concluded that NFKB recruits E2F1 to positively regulate a spectrum of NFKB target genes.
Using knockdown, transfection, and protein interaction experiments with human cell lines and mouse embryonic fibroblasts, Mao et al. (2009) showed that a complex of COMMD1 (607238), GCN5 (KAT2A; 602301), and CUL2 (603135) mediated ubiquitination of RELA, an event required for proper termination of RELA-promoter interactions. Chromatin immunoprecipitation experiments showed that COMMD1 or GCN5 deficiency prolonged promoter occupancy by RELA. IKK-dependent phosphorylation of RELA on ser468 enhanced binding of GCN5 to RELA and RELA ubiquitination.
Parker et al. (2014) showed that more than two-thirds of supratentorial ependymomas (see 137800) contain oncogenic fusions between RELA, the principal effector of canonic NFKB signaling (see 164011), and C11ORF95 (615699). In each case, C11ORF95-RELA fusions resulted from chromothripsis involving chromosome 11q13.1. C11ORF95-RELA fusion proteins translocated spontaneously to the nucleus to activate NFKB target genes, and rapidly transformed neural stem cells, the cells of origin of ependymomas, to form these tumors in mice. Parker et al. (2014) concluded that their data identified a highly recurrent genetic alteration of RELA in human cancer, and the C11ORF95-RELA fusion protein as a potential therapeutic target in supratentorial ependymoma.
Deloukas and van Loon (1993) determined the complete genomic structure of the human gene and a partial structure of the mouse gene encoding p65. The human gene consists of 10 exons and spans about 8.1 kb of DNA. A surprisingly high degree of conservation of intronic sequences was observed between the species. Variants generated by alternative splicing of intron 6 were observed in both species and the existence of another as yet unknown splice variant of p65 was predicted.
Using fluorescence in situ hybridization (FISH), Mathew et al. (1993) demonstrated that the NFKB3 gene is located on 11q13. Using a YAC containing the entire NFKB3 gene and FISH, Deloukas et al. (1994) found 2 sites of hybridization, 11q12 and Xp11.4, for sequences present in the YAC. The NFKB3 gene was assigned to 11q12 by PCR analysis of a panel of relevant hybrid cell lines.
Familial Behcet-Like Autoinflammatory Disease 3
In affected members of a family with familial Behcet-like autoinflammatory disease-3 (AIFBL3; 618287), Badran et al. (2017) identified a heterozygous splice site mutation in the RELA gene (164014.0001). Badran et al. (2017) designated the disorder chronic mucocutaneous ulceration (CMCU). Patient fibroblasts showed significantly more TNF-induced cell death and caspase-8 (610763) cleavage with significantly less NFKB activation compared to controls. There was selectively impaired survival of stromal cells, but not lymphocytes. IL6 (147620) secretion was impaired after TNF stimulation, consistent with impaired NFKB activation. Gene expression studies showed that patient fibroblasts had decreased upregulation of NFKB-dependent antiapoptotic genes after TNF exposure. The findings suggested that RELA haploinsufficiency causes impaired NFKB activity downstream of TNF activation, which results in impaired upregulation of antiapoptotic genes and increased stromal cell apoptosis. Thus, mucosal cells are dependent on biallelic RELA expression for protection against TNF-mediated cell death.
In an Irish family with AIFBL3, Adeeb et al. (2021) identified heterozygosity for a mutation in the RELA gene (c.1459delC; 164014.0003). When probed with an antibody targeting the N terminus of RELA, Western blot analysis in patient PBMCs demonstrated 2 bands, one corresponding to wildtype RELA and one corresponding to a truncated RELA protein. However, only the wildtype band was identified when probed with an antibody targeting the C terminus, corresponding to the loss of the C-terminal residues in the mutant protein. Compared to controls, patient PBMCs exhibited elevated RELA, TNFAIP3 (191163) and NFKBIA (164008) gene expression at baseline but reduced expression of these 3 genes after TNF induction. RELA with the c.1459delC mutation was transfected into HEK293 cells, and luciferase assays demonstrated reduced transcriptional activation in response to TNF compared to wildtype. The transfected cells also demonstrated increased apoptosis when exposed to TNF, with increased expression of BAX (600040) compared to wildtype.
In 7 members of a family with AIFBL3, Lecerf et al. (2023) identified heterozygosity for a mutation in the RELA gene (c.1004dupC; 164014.0003). The mutation was identified by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing. Lipopolysaccharide stimulation of patient derived PBMCs resulted in minimal phosphorylation of p65 and reduced pERK (see 601795) compared controls, which was consistent with RELA haploinsufficiency.
Associations Pending Confirmation
For discussion of a possible association between autoimmune lymphoproliferative syndrome (see, e.g., ALPS, 601859) and variation in the RELA gene, see 164014.0002.
Beg et al. (1995) made a transgenic knockout mouse line for RelA and showed that loss of the protein led to embryonic lethality at 15-16 days of gestation as a result of massive degeneration of the liver due to apoptosis.
Neurath et al. (1996) reported direct evidence for the involvement of p65 in chronic intestinal inflammation induced in mice and suggested a potential molecular therapeutic approach to the treatment of patients with Crohn disease (see 266600) using p65 antisense oligonucleotides.
In order to study the effect of Rela deficiency on mouse skin, Zhang et al. (2004) harvested Rela -/- embryo skin prior to embryonic lethality around embryonic day 15.5 and grafted it onto immune-deficient mice. Histologic examination revealed that Rela deficiency led to epidermal hyperplasia and moderately increased cell size. The granular and cornified layers appeared normal, and there was no inflammatory cell infiltration. Rela -/- keratinocytes exhibited enhanced proliferation in culture. Tnfr1 (191190)-dependent Jnk (601158) activation occurred in Rela -/- epidermis, and Jnk inhibition abolished hyperproliferation due to Rela deficiency. Furthermore, the hyperproliferation of Rela-deficient skin was completely reversed in Rela-Tnfr1 double-knockout skin. Zhang et al. (2004) concluded that RELA antagonizes TNFR1-JNK proliferative signals in epidermis and plays a nonredundant role in restraining epidermal growth.
Gugasyan et al. (2004) found that mutant mice lacking both c-rel and RelA displayed multiple epidermal defects, including thin epidermis and failure to form tylotrich hair. Although mutant keratinocytes underwent terminal differentiation, mutant basal keratinocytes were abnormally small, showed growth delay, and failed to form colonies in culture. The findings indicated that c-rel and RelA regulate skin development in a redundant manner and that both are required for normal epidermal development in mice.
Badran et al. (2017) found that haploinsufficient Rela +/- mice developed cutaneous ulcerations with epidermal skin loss and a predominance of neutrophils and macrophages in the dermis and hypodermis in response to TNF exposure. Studies with mutant mice who were chimeric for Rela indicated that the mucosal ulcerations were due to an epithelial and stromal cell defect, not a defect in bone marrow-derived immune cells.
In a mother and her 3 children with familial Behcet-like autoinflammatory disease-3 (AIFBL3; 618287), Badran et al. (2017) identified a heterozygous G-to-A transition in intron 6 of the RELA gene (c.559+1G-A, NM_021975), resulting in a splice site alteration. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP, 1000 Genomes Project, or ExAC databases. Patient cells showed a 50% reduction in RELA mRNA expression and protein levels, consistent with haploinsufficiency. Badran et al. (2017) designated the disorder chronic mucocutaneous ulceration.
This variant is classified as a variant of unknown significance because its contribution to autoimmune lymphoproliferative syndrome (see, e.g., ALPS, 601859) has not been confirmed.
In a boy who was diagnosed with autoimmune lymphoproliferative syndrome, Comrie et al. (2018) identified a de novo heterozygous c.736C-T transition (c.736C-T, NM_021975.3) in the RELA gene, resulting in an arg246-to-ter (R246X) substitution. The mutation, which was found by whole-genome sequencing, was associated with reduced RELA protein and mRNA, consistent with nonsense-mediated mRNA decay and haploinsufficiency. NFKB activation kinetics were similar to controls. Comrie et al. (2018) noted that the patient also had inherited multiple rare and potentially deleterious variants in genes affecting immune responses from the unaffected parents. The patient had refractory immune thrombocytopenic purpura (ITP), anemia, neutropenia, and splenomegaly. Additional features included episodic aseptic meningitis with lymphocytosis, and systemic symptoms, including headache. Immunologic workup showed enhanced T-cell activation and effector function with increased numbers of terminally differentiated T cells and enhanced T-helper cells. The patient did not have mucosal ulceration or inflammatory intestinal disease.
In 5 patients from 3 generations of an Irish family with familial Behcet-like autoinflammatory disease-3 (AIFBL3; 618287), Adeeb et al. (2021) identified heterozygosity for a 1-bp deletion (c.1459delC, ENST00000406346) in exon 11 of the RELA gene, resulting in a frameshift and premature termination (His487ThrfsTer7). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with disease in the family. The mutation was absent in the gnomAD database. When probed with an antibody targeting the N terminus of RELA, Western blotting in patient PBMCs demonstrated 2 bands, one corresponding to the wildtype RELA protein and one corresponding to a truncated RELA protein. However, only the wildtype band was identified when probed with an antibody targeting the C terminus, corresponding to loss of the C-terminal residues in the mutant protein. Patient PBMCs exhibited reduced TNF-induced expression of RELA compared to wildtype.
In 7 members of a family with familial Behcet-like familial autoinflammatory disease-3 (AIFBL3; 618287), Lecerf et al. (2023) identified heterozygosity for a 1-bp duplication (c.1004dupC, NM_021975.4) in the RELA gene, resulting in a frameshift and premature termination (Tyr349LeufsTer13). The mutation, which was identified by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing, segregated with disease in the family. The mutation was not present in the gnomAD database. Lipopolysaccharide stimulation of patient-derived PBMCs resulted in minimal phosphorylation of p65 and reduced pERK compared to controls, which was consistent with RELA haploinsufficiency.
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