RELB explained

Transcription factor RelB is a protein that in humans is encoded by the RELB gene.^[1]

Interactions

RELB has been shown to interact with NFKB2,^{[2] [3]} NFKB1,^[2] and C22orf25.^[4]

Activation and function

In resting cells, RelB is sequestered by the NF-κB precursor protein p100 in the cytoplasm. A select set of TNF-R superfamily members, including lymphotoxin β-receptor (LTβR), BAFF-R, CD40 and RANK, activate the non-canonical NF-κB pathway. In this pathway, NIK stimulates the processing of p100 into p52, which in association with RelB appears in the nucleus as RelB:p52 NF-κB heterodimers. RelB:p52 activates the expression homeostatic lymphokines,^[5] which instruct lymphoid organogenesis and determine the trafficking of naive lymphocytes in the secondary lymphoid organs.

Recent studies has suggested that the functional non-canonical NF-κB pathway is modulated by canonical NF-κB signalling. For example, syntheses of the constituents of the non-canonical pathway, viz RelB and p52, are controlled by canonical IKK2-IκB-RelA:p50 signalling.^[6] Moreover, generation of canonical and non-canonical dimers, viz RelA:p50 and RelB:p52, within the cellular milieu are mechanistically interlinked. These analyses suggest that an integrated NF-κB system network underlies activation of both RelA and RelB containing dimer and that a malfunctioning canonical pathway will lead to an aberrant cellular response also through the non-canonical pathway.

Most intriguingly, a recent study identified that TNF-induced canonical signalling subverts non-canonical RelB:p52 activity in the inflamed lymphoid tissues limiting lymphocyte ingress.^[7] Mechanistically, TNF inactivated NIK in LTβR‐stimulated cells and induced the synthesis of Nfkb2 mRNA encoding p100; these together potently accumulated unprocessed p100, which attenuated the RelB activity. A role of p100/Nfkb2 in dictating lymphocyte ingress in the inflamed lymphoid tissue may have broad physiological implications.

See also

• NF-κB

Further reading

• Taylor JP, Pomerantz R, Bagasra O, Chowdhury M, Rappaport J, Khalili K, Amini S . TAR-independent transactivation by Tat in cells derived from the CNS: a novel mechanism of HIV-1 gene regulation . The EMBO Journal . 11 . 9 . 3395–403 . September 1992 . 1505523 . 556874 . 10.1002/j.1460-2075.1992.tb05418.x.
• Ruben SM, Klement JF, Coleman TA, Maher M, Chen CH, Rosen CA . I-Rel: a novel rel-related protein that inhibits NF-kappa B transcriptional activity . Genes & Development . 6 . 5 . 745–60 . May 1992 . 1577270 . 10.1101/gad.6.5.745 . free .
• Liu J, Perkins ND, Schmid RM, Nabel GJ . Specific NF-kappa B subunits act in concert with Tat to stimulate human immunodeficiency virus type 1 transcription . Journal of Virology . 66 . 6 . 3883–7 . June 1992 . 1583734 . 241175 . 10.1128/JVI.66.6.3883-3887.1992 .
• Biswas DK, Salas TR, Wang F, Ahlers CM, Dezube BJ, Pardee AB . A Tat-induced auto-up-regulatory loop for superactivation of the human immunodeficiency virus type 1 promoter . Journal of Virology . 69 . 12 . 7437–44 . December 1995 . 7494249 . 189681 . 10.1128/JVI.69.12.7437-7444.1995 .
• Jeang KT, Chun R, Lin NH, Gatignol A, Glabe CG, Fan H . In vitro and in vivo binding of human immunodeficiency virus type 1 Tat protein and Sp1 transcription factor . Journal of Virology . 67 . 10 . 6224–33 . October 1993 . 7690421 . 238044 . 10.1128/JVI.67.10.6224-6233.1993 .
• Alcamí J, Laín de Lera T, Folgueira L, Pedraza MA, Jacqué JM, Bachelerie F, Noriega AR, Hay RT, Harrich D, Gaynor RB . 6 . Absolute dependence on kappa B responsive elements for initiation and Tat-mediated amplification of HIV transcription in blood CD4 T lymphocytes . The EMBO Journal . 14 . 7 . 1552–60 . April 1995 . 7729429 . 398242 . 10.1002/j.1460-2075.1995.tb07141.x.
• Majello B, De Luca P, Hagen G, Suske G, Lania L . Different members of the Sp1 multigene family exert opposite transcriptional regulation of the long terminal repeat of HIV-1 . Nucleic Acids Research . 22 . 23 . 4914–21 . November 1994 . 7800480 . 523756 . 10.1093/nar/22.23.4914 .
• Taylor JP, Pomerantz RJ, Oakes JW, Khalili K, Amini S . A CNS-enriched factor that binds to NF-kappa B and is required for interaction with HIV-1 tat . Oncogene . 10 . 2 . 395–400 . January 1995 . 7838536 .
• Westendorp MO, Shatrov VA, Schulze-Osthoff K, Frank R, Kraft M, Los M, Krammer PH, Dröge W, Lehmann V . 6 . HIV-1 Tat potentiates TNF-induced NF-kappa B activation and cytotoxicity by altering the cellular redox state . The EMBO Journal . 14 . 3 . 546–54 . February 1995 . 7859743 . 398112 . 10.1002/j.1460-2075.1995.tb07030.x.
• Scala G, Ruocco MR, Ambrosino C, Mallardo M, Giordano V, Baldassarre F, Dragonetti E, Quinto I, Venuta S . 6 . The expression of the interleukin 6 gene is induced by the human immunodeficiency virus 1 TAT protein . The Journal of Experimental Medicine . 179 . 3 . 961–71 . March 1994 . 8113688 . 2191426 . 10.1084/jem.179.3.961 .
• Bours V, Azarenko V, Dejardin E, Siebenlist U . Human RelB (I-Rel) functions as a kappa B site-dependent transactivating member of the family of Rel-related proteins . Oncogene . 9 . 6 . 1699–702 . June 1994 . 8183565 .
• Deloukas P, Dauwerse JG, van Ommen GJ, van Loon AP . The human NFKB3 gene encoding the p65 subunit of transcription factor NF-kappa B is located on chromosome 11q12 . Genomics . 19 . 3 . 592–4 . February 1994 . 8188306 . 10.1006/geno.1994.1115 .
• Westendorp MO, Li-Weber M, Frank RW, Krammer PH . Human immunodeficiency virus type 1 Tat upregulates interleukin-2 secretion in activated T cells . Journal of Virology . 68 . 7 . 4177–85 . July 1994 . 8207793 . 236340 . 10.1128/JVI.68.7.4177-4185.1994 .
• Dobrzanski P, Ryseck RP, Bravo R . Both N- and C-terminal domains of RelB are required for full transactivation: role of the N-terminal leucine zipper-like motif . Molecular and Cellular Biology . 13 . 3 . 1572–82 . March 1993 . 8441398 . 359469 . 10.1128/MCB.13.3.1572 .
• Harhaj E, Blaney J, Millhouse S, Sun SC . Differential effects of I kappa B molecules on Tat-mediated transactivation of HIV-1 LTR . Virology . 216 . 1 . 284–7 . February 1996 . 8615004 . 10.1006/viro.1996.0062 . free .
• Conant K, Ma M, Nath A, Major EO . Extracellular human immunodeficiency virus type 1 Tat protein is associated with an increase in both NF-kappa B binding and protein kinase C activity in primary human astrocytes . Journal of Virology . 70 . 3 . 1384–9 . March 1996 . 8627654 . 189957 . 10.1128/JVI.70.3.1384-1389.1996 .
• Demarchi F, d'Adda di Fagagna F, Falaschi A, Giacca M . Activation of transcription factor NF-kappaB by the Tat protein of human immunodeficiency virus type 1 . Journal of Virology . 70 . 7 . 4427–37 . July 1996 . 8676466 . 190376 . 10.1128/JVI.70.7.4427-4437.1996 .
• Beauparlant P, Kwon H, Clarke M, Lin R, Sonenberg N, Wainberg M, Hiscott J . Transdominant mutants of I kappa B alpha block Tat-tumor necrosis factor synergistic activation of human immunodeficiency virus type 1 gene expression and virus multiplication . Journal of Virology . 70 . 9 . 5777–85 . September 1996 . 8709193 . 190591 . 10.1128/JVI.70.9.5777-5785.1996 .
• Ramazzotti E, Vignoli M, Re MC, Furlini G, La Placa M . Enhanced nuclear factor-kappa B activation induced by tumour necrosis factor-alpha in stably tat-transfected cells is associated with the presence of cell-surface-bound Tat protein . AIDS . 10 . 5 . 455–61 . May 1996 . 8724035 . 10.1097/00002030-199605000-00002 . 84476590 .

Notes and References

1. Bours V, Burd PR, Brown K, Villalobos J, Park S, Ryseck RP, Bravo R, Kelly K, Siebenlist U . 6 . A novel mitogen-inducible gene product related to p50/p105-NF-kappa B participates in transactivation through a kappa B site . Molecular and Cellular Biology . 12 . 2 . 685–95 . February 1992 . 1531086 . 364259 . 10.1128/MCB.12.2.685 .
2. 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 . 6 . A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway . Nature Cell Biology . 6 . 2 . 97–105 . February 2004 . 14743216 . 10.1038/ncb1086 . 11683986 .
3. 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 . December 2003 . 14678988 .
4. Web site: Molecular Interaction Database. https://web.archive.org/web/20060506110418/http://mint.bio.uniroma2.it/mint/Welcome.do. dead. 2006-05-06.
5. Bonizzi G, Bebien M, Otero DC, Johnson-Vroom KE, Cao Y, Vu D, Jegga AG, Aronow BJ, Ghosh G, Rickert RC, Karin M . 6 . Activation of IKKalpha target genes depends on recognition of specific kappaB binding sites by RelB:p52 dimers . The EMBO Journal . 23 . 21 . 4202–10 . October 2004 . 15470505 . 524385 . 10.1038/sj.emboj.7600391 .
6. Basak S, Shih VF, Hoffmann A . Generation and activation of multiple dimeric transcription factors within the NF-kappaB signaling system . Molecular and Cellular Biology . 28 . 10 . 3139–50 . May 2008 . 18299388 . 2423155 . 10.1128/MCB.01469-07 .
7. Mukherjee T, Chatterjee B, Dhar A, Bais SS, Chawla M, Roy P, George A, Bal V, Rath S, Basak S . 6 . A TNF-p100 pathway subverts noncanonical NF-κB signaling in inflamed secondary lymphoid organs . The EMBO Journal . 36 . 23 . 3501–3516 . December 2017 . 29061763 . 5709727 . 10.15252/embj.201796919 .