Alternative titles; symbols
HGNC Approved Gene Symbol: NFKBIZ
Cytogenetic location: 3q12.3 Genomic coordinates (GRCh38) : 3:101,827,990-101,861,022 (from NCBI)
By subtraction cloning of interleukin-1-alpha (IL1A; 147760)-induced mouse stromal cells, Haruta et al. (2001) cloned Inap. The deduced 728-amino acid protein has a calculated molecular mass of about 79 kD. By database analysis, they identified human INAP. The human INAP protein has a 10-amino acid deletion compared with the mouse protein, and it has a calculated molecular mass of about 78 kD. Mouse and human INAP share 82% amino acid identity. Both proteins contain an N-terminal serine-rich region, followed by a PEST sequence, a glutamine-rich region, and 5 C-terminal ankyrin repeat motifs. INAP shares weak homology with the I-kappa-B (see IKBA; 164008) and Rel (see 164910) family of proteins, but it does not have the glycine-rich region, Rel homology domain, or nuclear localization signal commonly found in these proteins. Northern blot analysis did not detect Inap expression in any unstimulated mouse tissues examined; however, it was expressed by mouse stromal cells beginning 15 minutes after IL1A or IL1B (147720) stimulation. Western blot analysis detected a protein doublet of about 79 and 82 kD in IL1A-stimulated mouse stromal cells. The double bands were not affected by phosphatase treatment, and the authors suggested that the lower band may be a protein translated from a second met codon. Expression of human INAP was detected in IL1A-stimulated HeLa cell extracts.
Kitamura et al. (2000) cloned mouse Inap, which they called Mail. They noted that the C terminus of Mail shares homology with the I-kappa-B family and contains 6 ankyrin repeats. Yamazaki et al. (2001) also reported that mouse Inap, which they called I-kappa-B-zeta (IKBZ), contains 6 C-terminal ankyrin repeats.
By Northern blot analysis of unstimulated mouse tissues, Kitamura et al. (2000) detected expression of Mail only in testis. However, lipopolysaccharide (LPS) injection induced rapid expression of a 4.4-kb Mail transcript in numerous tissues, particularly spleen, lymph node, and lung. A smaller transcript, which was not affected by LPS injection, was also detected in testis. Ectopically expressed Mail had a nuclear localization and potentiated LPS-induced expression of Il6 (147620). Kitamura et al. (2002) found that enhanced Mail expression was accompanied by an increase in Tlr4 (603030) expression after LPS stimulation.
Haruta et al. (2001) determined that mouse Inap expression was rapidly and transiently induced in stromal cells by IL1A and IL1B, but not by tumor necrosis factor-alpha (TNFA; 191160) or phorbol esters. Fractionation of stimulated stromal cells and mouse fibroblasts overexpressing Inap suggested that newly synthesized Inap was rapidly translocated into the nucleus.
Yamazaki et al. (2001) found that Ikbz was induced in mouse macrophages following lipopolysaccharide stimulation. It was also stimulated by IL1B, but not TNFA. In contrast to cytosolic IKBA, IKBB (604495), and IKBE (605048), induced Ikbz localized in the nucleus via its N terminus. Transiently expressed Ikbz inhibited nuclear factor kappa-B (NFKB) activity without affecting the induced nuclear translocation of NFKB upon stimulation. Ikbz preferentially associated with NFKB subunit p50 (see 164011) rather than p65 (164014). Recombinant Ikbz inhibited DNA binding by the p65-p50 heterodimer and the p50-p50 homodimer.
Eto et al. (2003) found that pretreatment of a mouse macrophage cell line with NFKB inhibitors blocked induction of Ikbz by lipopolysaccharides. IKBZ was induced in human embryonic kidney cells by overexpression of MYD88 (602170) or TRAF6 (602355), but not TRAF2 (601895). In addition, induction was stimulated in mouse macrophages with peptidoglycan or CpG DNA, which activated Toll-like receptors Tlr2 (603028) and Tlr9 (605474), respectively.
Okamoto et al. (2010) identified I-kappa-B-zeta, encoded by the Nfkbiz gene, as a transcription factor required for Th17 development in mice. The ectopic expression of I-kappa-b-zeta in naive CD4+ T cells, together with ROR-gamma-t (602943) or ROR-alpha (600825), potently induced Th17 development, even in the absence of Il6 and Tgfb (190180). Notably, Nfkbiz-null mice have a defect in Th17 development and a resistance to experimental autoimmune encephalomyelitis. The T cell-intrinsic function of I-kappa-B-zeta was clearly demonstrated by the resistance to experimental autoimmune encephalomyelitis of the Rag2 (179616)-null mice into which Nfkbiz-null CD4+ T cells were transferred. In cooperation with Ror-gamma-t and ROR-alpha, I-kappa-B-zeta enhances Il17a (603149) expression by binding directly to the regulatory region of the Il17a gene.
Zhang et al. (2015) showed that TET2 (612839) selectively mediates active repression of IL6 (147620) transcription during inflammation resolution in innate myeloid cells, including dendritic cells and macrophages. I-kappa-B-zeta, an IL6-specific transcription factor, mediated specific targeting of Tet2 to the Il6 promoter, further indicating opposite regulatory roles of I-kappa-B-zeta at initial and resolution phases of inflammation.
Bambouskova et al. (2018) showed that itaconate and dimethylitaconate induce electrophilic stress, react with glutathione and subsequently induce both NRF2 (600492)-dependent and -independent responses. Bambouskova et al. (2018) found that electrophilic stress can selectively regulate secondary, but not primary, transcriptional responses to Toll-like receptor stimulation via inhibition of I-kappa-B-zeta protein induction. The regulation of I-kappa-B-zeta is independent of NRF2, and the authors identified ATF3 (603148) as its key mediator. The inhibitory effect is conserved across species and cell types, and the in vivo administration of dimethylitaconate could ameliorate IL17-I-kappa-B-zeta-driven skin pathology in a mouse model of psoriasis, highlighting the therapeutic potential of this regulatory pathway.
Using whole-exome sequencing data from 76 clonal human colon organoids, Nanki et al. (2020) identified a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis (see 266600). They found that the affected epithelia accumulated somatic mutations in multiple genes that are related to IL17 signaling, including NFKBIZ, ZC3H12A (610562), and PIGR (173880), which are genes that are rarely affected in colon cancer. Targeted sequencing validated the pervasive spread of mutations that are related to IL17 signaling. Unbiased CRISPR-based knockout screening in colon organoids revealed that the mutations conferred resistance to the proapoptotic response that is induced by IL17A. Some of these genetic mutations were known to exacerbate experimental colitis in mice, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Nanki et al. (2020) concluded that their findings highlighted a genetic landscape that adapts to a hostile microenvironment, and demonstrated its potential contribution to the pathogenesis of ulcerative colitis.
Kakiuchi et al. (2020) showed that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodeling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2 (607043), ZC3H12A, PIGR, and HNRNPF (601037) genes and are implicated in the downregulation of IL17 and other proinflammatory signals. Mutational profiles varied substantially between colitis-associated cancer and nondysplastic tissues in ulcerative colitis, which indicated that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ were highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in either sporadic or colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, Kakiuchi et al. (2020) found that tumor formation was significantly attenuated in Nfkbiz-mutant mice, and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Kakiuchi et al. (2020) concluded that their results highlighted common and discrete mechanisms of clonal selection in inflammatory tissues, which revealed unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.
Haruta et al. (2001) determined that the INAP gene contains 12 exons. Shiina et al. (2001) determined that the mouse Inap gene has 14 exons.
By genomic sequence analysis, Haruta et al. (2001) mapped the NFKBIZ gene to chromosome 3q13.11.
Gross (2020) mapped the NFKBIZ gene to chromosome 3q12.3 based on an alignment of the NFKBIZ sequence (GenBank BC060800) with the genomic sequence (GRCh38).
Shiina et al. (2001) mapped the mouse Inap gene to chromosome 16C1.2-C1.3 and the rat Inap gene to chromosome 11q21.1.
Yamamoto et al. (2004) found that Ikbz expression is strongly induced by a range of TLR (e.g., TLR4, 603030) agonists in addition to IL1 and lipopolysaccharide (LPS) but, unlike other Ikb family members, not by TNF, and not in Myd88 (602170) -/- fibroblasts. Splenocytes from mice lacking Ikbz failed to proliferate in response to LPS but had intact responses to anti-CD40 (109535), IL4 (147780), or anti-IgM (see 147020). The mutant mice were healthy until weeks 5 to 10, when they developed atopic dermatitis-like skin lesions with acanthosis and lichenoid changes accompanied by lymphocyte infiltration into the submucosa and loss of goblet cells in the conjunctival epithelium. Macrophages from Ikbz -/- mice produced normal amounts of TNF and nitric oxide but almost no IL6 in response to LPS. Kinetic analysis suggested that expression of IL6, but not of TNF, requires the preceding induction of Ikbz. Reporter analysis indicated that after stimulation with LPS, Ikbz binds only to the kappa-B site of IL6, whereas RelA (164014) and the p50 subunit of NF-kappa B (see 164011) also bind to the Elam1 (SELE; 131210) promoter site. Immunoprecipitation analysis showed that Ikbz interacts with NF-kappa-B p50, but not with RelA, RelB (604758), c-Rel (REL; 164910), or the p52 subunit of NF-kappa-B (NFKB2; 164012). Microarray and Northern blot analysis revealed that in Ikbz -/- macrophages stimulated with LPS, expression of Csf2 (138960), IL12b (161561), Csf3 (138970), Cebpd (116898), and Edn1 (131240), in addition to that of IL6, is compromised. Injection of Ikbz -/- mice with LPS demonstrated impaired IL12b production but, remarkably, almost normal serum IL6 and prolonged TNF production. IL6 levels could be reduced by treatment with antibodies to TNF. Yamamoto et al. (2004) proposed that the skin lesions in aged Ikbz-deficient mice might result from the prolonged TNF production.
Bambouskova, M., Gorvel, L., Lampropoulou, V., Sergushichev, A., Loginicheva, E., Johnson, K., Korenfeld, D., Mathyer, M. E., Kim, H., Huang, L.-H., Duncan, D., Bregman, H., and 19 others. Electrophilic properties of itaconate and derivatives regulate the I-kappa-B-zeta-ATF3 inflammatory axis. Nature 556: 501-504, 2018. [PubMed: 29670287] [Full Text: https://doi.org/10.1038/s41586-018-0052-z]
Eto, A., Muta, T., Yamazaki, S., Takeshige, K. Essential roles for NF-kappa-B and a Toll/IL-1 receptor domain-specific signal(s) in the induction of I-kappa-B-zeta. Biochem. Biophys. Res. Commun. 301: 495-501, 2003. [PubMed: 12565889] [Full Text: https://doi.org/10.1016/s0006-291x(02)03082-6]
Gross, M. B. Personal Communication. Baltimore, Md. 5/19/2020.
Haruta, H., Kato, A., Todokoro, K. Isolation of a novel interleukin-1-inducible nuclear protein bearing ankyrin-repeat motifs. J. Biol. Chem. 276: 12485-12488, 2001. [PubMed: 11278262] [Full Text: https://doi.org/10.1074/jbc.C100075200]
Kakiuchi, N., Yoshida, K., Uchino, M., Kihara, T., Akaki, K., Inoue, Y., Kawada, K., Nagayama, S., Yokoyama, A., Yamamoto, S., Matsuura, M., Horimatsu, T., and 42 others. Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis. Nature 577: 260-265, 2020. [PubMed: 31853061] [Full Text: https://doi.org/10.1038/s41586-019-1856-1]
Kitamura, H., Kanehira, K., Okita, K., Morimatsu, M., Saito, M. MAIL, a novel nuclear I-kappa-B protein that potentiates LPS-induced IL-6 production. FEBS Lett. 485: 53-56, 2000. [PubMed: 11086164] [Full Text: https://doi.org/10.1016/s0014-5793(00)02185-2]
Kitamura, H., Kanehira, K., Shiina, T., Morimatsu, M., Jung, B. D., Akashi, S., Saito, M. Bacterial lipopolysaccharide induces mRNA expression of an IkappaB MAIL through toll-like receptor 4. J. Vet. Med. Sci. 64: 419-422, 2002. [PubMed: 12069074] [Full Text: https://doi.org/10.1292/jvms.64.419]
Nanki, K., Fujii, M., Shimokawa, M., Matano, M., Nishikori, S., Date, S., Takano, A., Toshimitsu, K., Ohta, Y., Takahashi, S., Sugimoto, S., Ishimaru, K., and 9 others. Somatic inflammatory gene mutations in human ulcerative colitis epithelium. Nature 577: 254-259, 2020. [PubMed: 31853059] [Full Text: https://doi.org/10.1038/s41586-019-1844-5]
Okamoto, K., Iwai, Y., Oh-hora, M., Yamamoto, M., Morio, T., Aoki, K., Ohya, K., Jetten, A. M., Akira, S., Muta, T., Takayanagi, H. I-kappa-B-zeta regulates T(H)17 development by cooperating with ROR nuclear receptors. Nature 464: 1381-1385, 2010. [PubMed: 20383124] [Full Text: https://doi.org/10.1038/nature08922]
Shiina, T., Morimatsu, M., Kitamura, H., Ito, T., Kidou, S., Matsubara, K., Matsuda, Y., Saito, M., Syuto, B. Genomic organization, chromosomal localization, and promoter analysis of the mouse Mail gene. Immunogenetics 53: 649-655, 2001. [PubMed: 11797098] [Full Text: https://doi.org/10.1007/s00251-001-0376-x]
Yamamoto, M., Yamazaki, S., Uematsu, S., Sato, S., Hemmi, H., Hoshino, K., Kaisho, T., Kuwata, H., Takeuchi, O., Takeshige, K., Saitoh, T., Yamaoka, S., Yamamoto, N., Yamamoto, S., Muta, T., Takeda, K., Akira, S. Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein I-kappa-B-zeta. Nature 430: 218-222, 2004. [PubMed: 15241416] [Full Text: https://doi.org/10.1038/nature02738]
Yamazaki, S., Muta, T., Takeshige, K. A novel I-kappa-B protein, I-kappa-B-zeta, induced by proinflammatory stimuli, negatively regulates nuclear factor-kappa-B in the nuclei. J. Biol. Chem. 276: 27657-27662, 2001. [PubMed: 11356851] [Full Text: https://doi.org/10.1074/jbc.M103426200]
Zhang, Q., Zhao, K., Shen, Q., Han, Y., Gu, Y., Li, X., Zhao, D., Liu, Y., Wang, C., Zhang, X., Su, X., Liu, J., Ge, W., Levine, R. L., Li, N., Cao, X. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature 525: 389-393, 2015. [PubMed: 26287468] [Full Text: https://doi.org/10.1038/nature15252]