IκBα explained

IκBα (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha; NFKBIA) is one member of a family of cellular proteins that function to inhibit the NF-κB transcription factor. IκBα inhibits NF-κB by masking the nuclear localization signals (NLS) of NF-κB proteins and keeping them sequestered in an inactive state in the cytoplasm.^[1] In addition, IκBα blocks the ability of NF-κB transcription factors to bind to DNA, which is required for NF-κB's proper functioning.^[2]

Disease linkage

The gene encoding the IκBα protein is mutated in some Hodgkin's lymphoma cells; such mutations inactivate the IκBα protein, thus causing NF-κB to be chronically active in the lymphoma tumor cells and this activity contributes to the malignant state of these tumor cells.^[3]

Interactions

IκBα has been shown to interact with:

• BTRC,^{[4] [5]}
• C22orf25,^[6]
• CHUK,^{[7] [8]}
• DYNLL1,^[9]
• G3BP2,^[10]
• Heterogeneous nuclear ribonucleoprotein A1,
• IKK2,^{[11] [12] [13]}
• NFKB1,
• P53,^[14]
• RELA,^{[5] [11] [15] [16] [17] [18] [19]}
• RPS6KA1,^[20]
• SUMO4,^[21] and
• Valosin-containing protein.^[22]

Further reading

• Roulston A, Lin R, Beauparlant P, Wainberg MA, Hiscott J . Regulation of human immunodeficiency virus type 1 and cytokine gene expression in myeloid cells by NF-kappa B/Rel transcription factors. . Microbiol. Rev. . 59 . 3 . 481–505 . 1995 . 7565415 . 239370 . 10.1128/MMBR.59.3.481-505.1995.
• Hay RT, Vuillard L, Desterro JM, Rodriguez MS . Control of NF-kappa B transcriptional activation by signal induced proteolysis of I kappa B alpha. . Philos. Trans. R. Soc. Lond. B Biol. Sci. . 354 . 1389 . 1601–9 . 2000 . 10582246 . 1692667 . 10.1098/rstb.1999.0504 .
• Muthumani K, Desai BM, Hwang DS, Choo AY, Laddy DJ, Thieu KP, Rao RG, Weiner DB . HIV-1 Vpr and anti-inflammatory activity. . DNA Cell Biol. . 23 . 4 . 239–47 . 2004 . 15142381 . 10.1089/104454904773819824 .
• Caraglia M, Marra M, Pelaia G, Maselli R, Caputi M, Marsico SA, Abbruzzese A . Alpha-interferon and its effects on signal transduction pathways. . J. Cell. Physiol. . 202 . 2 . 323–35 . 2005 . 15389589 . 10.1002/jcp.20137 . free .
• Le Rouzic E, Benichou S . The Vpr protein from HIV-1: distinct roles along the viral life cycle. . Retrovirology . 2 . 1 . 11 . 2006 . 15725353 . 554975 . 10.1186/1742-4690-2-11 . free .
• Zhao RY, Bukrinsky M, Elder RT . HIV-1 viral protein R (Vpr) & host cellular responses. . Indian J. Med. Res. . 121 . 4 . 270–86 . 2005 . 15817944 .
• Sun XF, Zhang H . NFKB and NFKBI polymorphisms in relation to susceptibility of tumour and other diseases. . Histol. Histopathol. . 22 . 12 . 1387–98 . 2007 . 17701919 .

External links

• OMIM entries on Ectodermal Dysplasia, Anhidrotic, with T-cell Immunodeficiency

Notes and References

1. Jacobs MD, Harrison SC . Structure of an IkappaBalpha/NF-kappaB complex . Cell . 95 . 6 . 749–58 . 1998 . 9865693 . 10.1016/S0092-8674(00)81698-0 . 7003353 . free .
2. Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S . Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation . Genes Dev. . 9 . 22 . 2723–35 . 1995 . 7590248 . 10.1101/gad.9.22.2723 . free .
3. Cabannes E, Khan G, Aillet F, Jarrett RF, Hay RT . Mutations in the IkBa gene in Hodgkin's disease suggest a tumour suppressor role for IkappaBalpha . Oncogene . 18 . 20 . 3063–70 . 1999 . 10340377 . 10.1038/sj.onc.1202893 . 8269256 .
4. Suzuki H, Chiba T, Suzuki T, Fujita T, Ikenoue T, Omata M, Furuichi K, Shikama H, Tanaka K . Homodimer of two F-box proteins betaTrCP1 or betaTrCP2 binds to IkappaBalpha for signal-dependent ubiquitination . J. Biol. Chem. . 275 . 4 . 2877–84 . January 2000 . 10644755 . 10.1074/jbc.275.4.2877. free .
5. Spencer E, Jiang J, Chen ZJ . Signal-induced ubiquitination of IkappaBalpha by the F-box protein Slimb/beta-TrCP . Genes Dev. . 13 . 3 . 284–94 . February 1999 . 9990853 . 316434 . 10.1101/gad.13.3.284.
6. Web site: Molecular Interaction Database. 2012-05-08. https://web.archive.org/web/20060506110418/http://mint.bio.uniroma2.it/mint/Welcome.do. 2006-05-06. dead.
7. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M . A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB . Nature . 388 . 6642 . 548–54 . August 1997 . 9252186 . 10.1038/41493 . 4354442 . free .
8. Ninomiya-Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K . The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway . Nature . 398 . 6724 . 252–6 . March 1999 . 10094049 . 10.1038/18465 . 1999Natur.398..252N . 4421236 .
9. Crépieux P, Kwon H, Leclerc N, Spencer W, Richard S, Lin R, Hiscott J . I kappaB alpha physically interacts with a cytoskeleton-associated protein through its signal response domain . Mol. Cell. Biol. . 17 . 12 . 7375–85 . December 1997 . 9372968 . 232593 . 10.1128/MCB.17.12.7375.
10. Prigent M, Barlat I, Langen H, Dargemont C . IkappaBalpha and IkappaBalpha /NF-kappa B complexes are retained in the cytoplasm through interaction with a novel partner, RasGAP SH3-binding protein 2 . J. Biol. Chem. . 275 . 46 . 36441–9 . November 2000 . 10969074 . 10.1074/jbc.M004751200 . free .
11. Cohen L, Henzel WJ, Baeuerle PA . IKAP is a scaffold protein of the IkappaB kinase complex . Nature . 395 . 6699 . 292–6 . September 1998 . 9751059 . 10.1038/26254 . 1998Natur.395..292C . 4327300 .
12. Woronicz JD, Gao X, Cao Z, Rothe M, Goeddel DV . IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK . Science . 278 . 5339 . 866–9 . October 1997 . 9346485 . 10.1126/science.278.5339.866. 1997Sci...278..866W .
13. Mercurio F, Murray BW, Shevchenko A, Bennett BL, Young DB, Li JW, Pascual G, Motiwala A, Zhu H, Mann M, Manning AM . IkappaB kinase (IKK)-associated protein 1, a common component of the heterogeneous IKK complex . Mol. Cell. Biol. . 19 . 2 . 1526–38 . February 1999 . 9891086 . 116081 . 10.1128/mcb.19.2.1526.
14. Chang NS . The non-ankyrin C terminus of Ikappa Balpha physically interacts with p53 in vivo and dissociates in response to apoptotic stress, hypoxia, DNA damage, and transforming growth factor-beta 1-mediated growth suppression . J. Biol. Chem. . 277 . 12 . 10323–31 . March 2002 . 11799106 . 10.1074/jbc.M106607200 . free .
15. Hay DC, Kemp GD, Dargemont C, Hay RT . Interaction between hnRNPA1 and IkappaBalpha is required for maximal activation of NF-kappaB-dependent transcription . Mol. Cell. Biol. . 21 . 10 . 3482–90 . May 2001 . 11313474 . 100270 . 10.1128/MCB.21.10.3482-3490.2001 .
16. Malek S, Huxford T, Ghosh G . Ikappa Balpha functions through direct contacts with the nuclear localization signals and the DNA binding sequences of NF-kappaB . J. Biol. Chem. . 273 . 39 . 25427–35 . September 1998 . 9738011 . 10.1074/jbc.273.39.25427. free .
17. Fischle W, Verdin E, Greene WC . Duration of nuclear NF-kappaB action regulated by reversible acetylation . Science . 293 . 5535 . 1653–7 . August 2001 . 11533489 . 10.1126/science.1062374 . 2001Sci...293.1653C . 11858/00-001M-0000-002C-9FF1-A . 45796404 . free .
18. Kiernan R, Brès V, Ng RW, Coudart MP, El Messaoudi S, Sardet C, Jin DY, Emiliani S, Benkirane M . Post-activation turn-off of NF-kappa B-dependent transcription is regulated by acetylation of p65 . J. Biol. Chem. . 278 . 4 . 2758–66 . January 2003 . 12419806 . 10.1074/jbc.M209572200 . free .
19. Hansen SK, Baeuerle PA, Blasi F . Purification, reconstitution, and I kappa B association of the c-Rel-p65 (RelA) complex, a strong activator of transcription . Mol. Cell. Biol. . 14 . 4 . 2593–603 . April 1994 . 8139561 . 358627 . 10.1128/mcb.14.4.2593.
20. Schouten GJ, Vertegaal AC, Whiteside ST, Israël A, Toebes M, Dorsman JC, van der Eb AJ, Zantema A . IkappaB alpha is a target for the mitogen-activated 90 kDa ribosomal S6 kinase . EMBO J. . 16 . 11 . 3133–44 . June 1997 . 9214631 . 1169932 . 10.1093/emboj/16.11.3133 .
21. Guo D, Li M, Zhang Y, Yang P, Eckenrode S, Hopkins D, Zheng W, Purohit S, Podolsky RH, Muir A, Wang J, Dong Z, Brusko T, Atkinson M, Pozzilli P, Zeidler A, Raffel LJ, Jacob CO, Park Y, Serrano-Rios M, Larrad MT, Zhang Z, Garchon HJ, Bach JF, Rotter JI, She JX, Wang CY . A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes . Nat. Genet. . 36 . 8 . 837–41 . August 2004 . 15247916 . 10.1038/ng1391 . 41123857 .
22. Dai RM, Chen E, Longo DL, Gorbea CM, Li CC . Involvement of valosin-containing protein, an ATPase Co-purified with IkappaBalpha and 26 S proteasome, in ubiquitin-proteasome-mediated degradation of IkappaBalpha . J. Biol. Chem. . 273 . 6 . 3562–73 . February 1998 . 9452483 . 10.1074/jbc.273.6.3562. free .