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,[9] 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.[10] 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.[11] 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.
^ abBouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, et al. (February 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology. 6 (2): 97–105. doi:10.1038/ncb1086. PMID14743216. S2CID11683986.
^Thornburg NJ, Pathmanathan R, Raab-Traub N (December 2003). "Activation of nuclear factor-kappaB p50 homodimer/Bcl-3 complexes in nasopharyngeal carcinoma". Cancer Research. 63 (23): 8293–301. PMID14678988.
Taylor JP, Pomerantz RJ, Oakes JW, Khalili K, Amini S (January 1995). "A CNS-enriched factor that binds to NF-kappa B and is required for interaction with HIV-1 tat". Oncogene. 10 (2): 395–400. PMID7838536.
Bours V, Azarenko V, Dejardin E, Siebenlist U (June 1994). "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. PMID8183565.
Deloukas P, Dauwerse JG, van Ommen GJ, van Loon AP (February 1994). "The human NFKB3 gene encoding the p65 subunit of transcription factor NF-kappa B is located on chromosome 11q12". Genomics. 19 (3): 592–4. doi:10.1006/geno.1994.1115. PMID8188306.
Ramazzotti E, Vignoli M, Re MC, Furlini G, La Placa M (May 1996). "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. doi:10.1097/00002030-199605000-00002. PMID8724035. S2CID84476590.
PDB gallery
1zk9: NF-kB RelB forms an intertwined homodimer
1zka: NF-kB RelB forms an intertwined homodimer, Y300S mutant
