NFKB2 explained

Nuclear factor NF-kappa-B p100 subunit is a protein that in humans is encoded by the NFKB2 gene.^[1]

Function

NF-κB has been detected in numerous cell types that express cytokines, chemokines, growth factors, cell adhesion molecules, and some acute phase proteins in health and in various disease states. NF-κB is activated by a wide variety of stimuli such as cytokines, oxidant-free radicals, inhaled particles, ultraviolet irradiation, and bacterial or viral products. Inappropriate activation of NF-kappa-B has been linked to inflammatory events associated with autoimmune arthritis, asthma, septic shock, lung fibrosis, glomerulonephritis, atherosclerosis, and AIDS. In contrast, complete and persistent inhibition of NF-kappa-B has been linked directly to apoptosis, inappropriate immune cell development, and delayed cell growth. For reviews, see Chen et al. (1999) and Baldwin (1996).[supplied by OMIM]^[2]

Clinical significance

Mutation of the NFKB2 gene has been linked to Common variable immunodeficiency (CVID) as the cause of the disease. Other genes might also be responsible. The frequency of NFKB2 mutation in CVID population is yet to be established.^[3]

The protein NFKB2 can become mutated and lead to hereditary endocrine and immuneodeficiences.^[4] The mutation occurs at the C-terminus of NFKB2 and it causes common variable immunodeficienciency which in turn causes endocrine deficiency and immunodeficiencies. A NFKB2 mutation can cause things like adrenocorticotropic hormone deficiency and DAVID syndrome which is a pituitary hormone deficiency and CVID.^[5]

The mutations that occur within the C-terminus affect the serine 866 and 870. These serines are considered phosphorylation sites for NFKB2. These mutations at the serine's in the C-terminus lead to CVID in combination with other endocrine deficiencies. These endocrine deficiencies along with the mutation of NFKB2, lead scientists to believe that mutation of NFKB2 is a rare hereditary disease called DAVID's disease.

Interactions

NFKB2 has been shown to interact with:

• BCL3,^{[6] [7]}
• BTRC,^{[8] [9]}
• MAP3K8,^[10]
• NFKB1,^[10]
• NFKBIE,^[11]
• RELA,^{[10] [12]}
• RELB,^{[6] [10]}
• REL,^{[10] [12]} and
• TSC22D3.^[13]

See also

• NF-κB
• DAVID syndrome

Further reading

• Schreck R, Albermann K, Baeuerle PA . Nuclear factor kappa B: an oxidative stress-responsive transcription factor of eukaryotic cells (a review) . Free Radical Research Communications . 17 . 4 . 221–37 . 1993 . 1473734 . 10.3109/10715769209079515 .
• Baldwin AS . The NF-kappa B and I kappa B proteins: new discoveries and insights . Annual Review of Immunology . 14 . 1 . 649–83 . 1996 . 8717528 . 10.1146/annurev.immunol.14.1.649 .
• Chen F, Castranova V, Shi X, Demers LM . New insights into the role of nuclear factor-kappaB, a ubiquitous transcription factor in the initiation of diseases . Clinical Chemistry . 45 . 1 . 7–17 . Jan 1999 . 9895331 . 10.1093/clinchem/45.1.7. free .
• Bottex-Gauthier C, Pollet S, Favier A, Vidal DR . [The Rel/NF-kappa-B transcription factors: complex role in cell regulation] . Pathologie-Biologie . 50 . 3 . 204–11 . Apr 2002 . 11980335 . 10.1016/s0369-8114(02)00289-4 .
• Garg A, Aggarwal BB . Nuclear transcription factor-kappaB as a target for cancer drug development . Leukemia . 16 . 6 . 1053–68 . Jun 2002 . 12040437 . 10.1038/sj.leu.2402482 . 9560168 .

Notes and References

1. Schmid RM, Perkins ND, Duckett CS, Andrews PC, Nabel GJ . Cloning of an NF-kappa B subunit which stimulates HIV transcription in synergy with p65 . Nature . 352 . 6337 . 733–6 . Aug 1991 . 1876189 . 10.1038/352733a0 . 1991Natur.352..733S . 2027.42/62829 . 4237376 . free .
2. Web site: Entrez Gene: NFKB2 nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (p49/p100).
3. Chen K, Coonrod EM, Kumánovics A, Franks ZF, Durtschi JD, Margraf RL, Wu W, Heikal NM, Augustine NH, Ridge PG, Hill HR, Jorde LB, Weyrich AS, Zimmerman GA, Gundlapalli AV, Bohnsack JF, Voelkerding KV . Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency . American Journal of Human Genetics . 93 . 5 . 812–24 . Nov 2013 . 24140114 . 10.1016/j.ajhg.2013.09.009 . 3824125.
4. Brue T, Quentien MH, Khetchoumian K, Bensa M, Capo-Chichi JM, Delemer B, Balsalobre A, Nassif C, Papadimitriou DT, Pagnier A, Hasselmann C, Patry L, Schwartzentruber J, Souchon PF, Takayasu S, Enjalbert A, Van Vliet G, Majewski J, Drouin J, Samuels ME . Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies . BMC Medical Genetics . 15 . 139 . December 2014 . 25524009 . 4411703 . 10.1186/s12881-014-0139-9 . free .
5. Shi C, Wang F, Tong A, Zhang XQ, Song HM, Liu ZY, Lyu W, Liu YH, Xia WB . NFKB2 mutation in common variable immunodeficiency and isolated adrenocorticotropic hormone deficiency: A case report and review of literature . Medicine . 95 . 40 . e5081 . October 2016 . 27749582 . 10.1097/md.0000000000005081 . 5059085.
6. Thornburg NJ, Pathmanathan R, Raab-Traub N . Activation of nuclear factor-kappaB p50 homodimer/Bcl-3 complexes in nasopharyngeal carcinoma . Cancer Research . 63 . 23 . 8293–301 . Dec 2003 . 14678988 .
7. Bours V, Franzoso G, Azarenko V, Park S, Kanno T, Brown K, Siebenlist U . The oncoprotein Bcl-3 directly transactivates through kappa B motifs via association with DNA-binding p50B homodimers . Cell . 72 . 5 . 729–39 . Mar 1993 . 8453667 . 10.1016/0092-8674(93)90401-b. free .
8. Fong A, Sun SC . Genetic evidence for the essential role of beta-transducin repeat-containing protein in the inducible processing of NF-kappa B2/p100 . The Journal of Biological Chemistry . 277 . 25 . 22111–4 . Jun 2002 . 11994270 . 10.1074/jbc.C200151200 . free .
9. Vatsyayan J, Qing G, Xiao G, Hu J . SUMO1 modification of NF-kappaB2/p100 is essential for stimuli-induced p100 phosphorylation and processing . EMBO Reports . 9 . 9 . 885–90 . Sep 2008 . 18617892 . 2529344 . 10.1038/embor.2008.122 .
10. Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G . A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway . Nature Cell Biology . 6 . 2 . 97–105 . Feb 2004 . 14743216 . 10.1038/ncb1086 . 11683986 .
11. Li Z, Nabel GJ . A new member of the I kappaB protein family, I kappaB epsilon, inhibits RelA (p65)-mediated NF-kappaB transcription . Molecular and Cellular Biology . 17 . 10 . 6184–90 . Oct 1997 . 9315679 . 232469 . 10.1128/mcb.17.10.6184.
12. Scheinman RI, Beg AA, Baldwin AS . NF-kappa B p100 (Lyt-10) is a component of H2TF1 and can function as an I kappa B-like molecule . Molecular and Cellular Biology . 13 . 10 . 6089–101 . Oct 1993 . 8413211 . 364669 . 10.1128/mcb.13.10.6089.
13. Ayroldi E, Migliorati G, Bruscoli S, Marchetti C, Zollo O, Cannarile L, D'Adamio F, Riccardi C . Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor kappaB . Blood . 98 . 3 . 743–53 . Aug 2001 . 11468175 . 10.1182/blood.v98.3.743. free .