Alternative titles; symbols
HGNC Approved Gene Symbol: NFKBIE
Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38): 6:44,258,166-44,265,551 (from NCBI)
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, 603258) 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). For some genes, activation requires NFKB interaction with other transcription factors, such as STAT (see STAT6, 601512), AP1 (JUN, 165160), and NFAT (see NFATC1, 600489).
Using the yeast 2-hybrid system to screen a human PBL-derived cDNA library, Whiteside et al. (1997) identified a novel I-kappa-B family member, NFKBIE, which they termed I-kappa-B epsilon. NFKBIE is expressed as a 45-kD protein, which exists as multiple phosphorylated isoforms in resting cells and complexes predominantly with RELA and REL. The deduced 361-amino acid protein contains 6 closely spaced ankyrin repeats and 2 serine residues at positions 18 and 22, but no C-terminal PEST residues. Stimulation of cells with LPS or phorbol esters results in the proteolytic degradation of NFKBIE. Northern blot analysis revealed expression of a 2.2-kb transcript in all cells tested.
Independently, Li and Nabel (1997) cloned NFKBIE. They detected 2.2- and 2.8-kb transcripts of NFKBIE by Northern blot analysis and found that the protein interacted most strongly with RELA and REL but also with NFKB1 and NFKB2.
Using electrophoretic mobility shift analysis (EMSA), Hoffmann et al. (2002) showed that persistent stimulation of T cells, monocytes, or fibroblasts with TNFA (191160) resulted in the coordinated degradation, synthesis, and localization of IKBA, IKBB, and IKBE necessary to generate the characteristic NFKB activation profile.
Hoffmann et al. (2002) generated mice deficient in Ikbb and Ikbe by homologous recombination and intercrossed them with Ikba-deficient mice to yield embryonic fibroblasts containing only 1 Ikb isoform. TNFA stimulation of the Ikba fibroblasts resulted in a highly oscillatory Nfkb response, whereas in Ikbb and Ikbe fibroblasts nuclear Nfkb increased monotonically. Hoffmann et al. (2002) concluded that IKBA mediates rapid NFKB activation and strong negative feedback regulation, while IKBB and IKBE respond more slowly to IKK activation and act to dampen long-term oscillations of the NFKB response. Computational and EMSA analyses revealed bimodal signal-processing characteristics with respect to the duration of the stimulus, enabling the generation of specificity in gene expression of IP10 (CXCL10; 147310) and RANTES (CCL5; 187011). In a commentary, Ting and Endy (2002) compared the duration of signaling to the creation of an audible tone by pressing a piano key, which causes a hammer to hit a string. How hard the string is hit, and whether or not string vibration is sustained after the key is released, can be modified by depressing a foot pedal, much as signal transduction pathways are activated and modified by information in the environment.
Hoffmann, A., Levchenko, A., Scott, M. L., Baltimore, D. The I-kappa-B-NF-kappa-B signaling module: temporal control and selective gene activation. Science 298: 1241-1245, 2002. Note: Erratum: Science 318: 1550 only, 2007. [PubMed: 12424381] [Full Text: https://doi.org/10.1126/science.1071914]
Li, Z., Nabel, G. J. A new member of the I-kappa-B protein family, I-kappa-B epsilon, inhibits RelA (p65)-mediated NF-kappa-B transcription. Molec. Cell. Biol. 17: 6184-6190, 1997. [PubMed: 9315679] [Full Text: https://doi.org/10.1128/MCB.17.10.6184]
Ting, A. Y., Endy, D. Decoding NF-kappa-B signaling. Science 298: 1189-1190, 2002. [PubMed: 12424362] [Full Text: https://doi.org/10.1126/science.1079331]
Whiteside, S. T., Epinat, J.-C., Rice, N. R., Israel, A. I-kappa-B epsilon, a novel member of the I-kappa-B family, controls RelA and cRel NF-kappa-B activity. EMBO J. 16: 1413-1426, 1997. [PubMed: 9135156] [Full Text: https://doi.org/10.1093/emboj/16.6.1413]