Alternative titles; symbols
HGNC Approved Gene Symbol: NFKBIB
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38): 19:38,899,666-38,908,889 (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), 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).
Lee et al. (1995) identified NFKBIB, also known as NF-kappa-BIB, as a protein, which they designated TRIP9 for 'thyroid hormone receptor interacting protein-9,' that specifically interacted with the ligand-binding domain of thyroid hormone receptor-beta (190160). TRIP9 interaction with the thyroid hormone receptor was dependent upon the presence of thyroid hormone. TRIP9 contains 3 ankyrin repeats and is most closely related to BCL3 (109560). Northern blot analysis revealed that TRIP9 was expressed as 2.8- and 1.8-kb transcripts in all tissues examined.
Using a yeast 2-hybrid screen with p65 (164014) as bait, Okamoto et al. (1998) isolated a full-length NFKBIB cDNA clone from a human placenta Matchmaker cDNA library. The NFKBIB cDNA is 1,940 bp.
Fenwick et al. (2000) identified 2 proteins, KBRAS1 (604496) and KBRAS2 (604497), which interacted with the PEST domains of I-kappa-B-alpha and I-kappa-B-beta and decreased their rate of degradation. In cells, KBRAS proteins associated only with NF-kappa-B:I-kappa-B complexes; the authors suggested that therefore this may provide an explanation for the slower rate of degradation of I-kappa-B-beta compared with that of I-kappa-B-alpha.
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 (604548) necessary to generate the characteristic NFKB activation profile.
Rao et al. (2010) reported that in vivo, I-kappa-B-beta serves both to inhibit and to facilitate the inflammatory response. I-kappa-B-beta degradation releases NF-kappa-B dimers, which upregulate proinflammatory target genes such as TNF-alpha. Surprisingly, absence of I-kappa-B-beta results in a dramatic reduction of TNF-alpha in response to lipopolysaccharide, even though activation of NF-kappa-B is normal. The inhibition of TNF-alpha mRNA expression correlates with the absence of nuclear, hypophosphorylated I-kappa-B-beta bound to p65 (164014):c-Rel (164910) heterodimers at a specific kappa-B site on the TNF-alpha promoter. Therefore, I-kappa-B-beta acts through p65:c-Rel dimers to maintain prolonged expression of TNF-alpha. As a result, I-kappa-B-beta-null mice are resistant to lipopolysaccharide-induced septic shock and collagen-induced arthritis.
By fluorescence in situ hybridization, Okamoto et al. (1998) mapped the NFKBIB gene to 19q13.1, in close proximity to the BCL3 gene. They suggested the likelihood that the 2 genes share the same ancestral origin and that they were generated by localized gene duplication.
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.
Fenwick, C., Na, S.-Y., Voll, R. E., Zhong, H., Im, S.-Y., Lee, J. W., Ghosh, S. A subclass of Ras proteins that regulate the degradation of I-kappa-B. Science 287: 869-873, 2000. [PubMed: 10657303] [Full Text: https://doi.org/10.1126/science.287.5454.869]
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]
Lee, J. W., Choi, H.-S., Gyuris, J., Brent, R., Moore, D. D. Two classes of proteins dependent on either the presence or absence of thyroid hormone for interaction with the thyroid hormone receptor. Molec. Endocr. 9: 243-254, 1995. [PubMed: 7776974] [Full Text: https://doi.org/10.1210/mend.9.2.7776974]
Okamoto, T., Ono, T., Hori, M., Yang, J.-P., Tetsuka, T., Kawabe, T., Sonta, S. Assignment of the I-kappa-B-beta gene NFKBIB to human chromosome band 19q13.1 by in situ hybridization. Cytogenet. Cell Genet. 82: 105-106, 1998. [PubMed: 9763672] [Full Text: https://doi.org/10.1159/000015077]
Rao, P., Hayden, M. S., Long, M., Scott, M. L., West, A. P., Zhang, D., Oeckinghaus, A., Lynch, C., Hoffmann, A., Baltimore, D., Ghosh, S. I-kappa-B-beta acts to inhibit and activate gene expression during the inflammatory response. Nature 466: 1115-1119, 2010. [PubMed: 20740013] [Full Text: https://doi.org/10.1038/nature09283]
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]