RelB/p50 dimers are differentially regulated by tumor necrosis factor-alpha and lymphotoxin-beta receptor activation: critical roles for p100.
Tumor necrosis factor-alpha (TNF-alpha) and lymphotoxin-beta receptor (LTbetaR) signaling both play important roles in inflammatory and immune responses through activation of NF-kappaB. Using various deficient mouse embryonic fibroblast cells, we have compared the signaling pathways leading to NF-kappaB induction in response to TNF-alpha and LTbetaR activation. We demonstrate that LTbetaR ligation induces not only RelA/p50 dimers but also RelB/p50 dimers, whereas TNF-alpha induces only RelA/p50 dimers. LTbetaR-induced binding of RelB/p50 requires processing of p100 that is mediated by IKKalpha but is independent of IKKbeta, NEMO/IKKgamma, and RelA. Moreover, we show that RelB, p50, and p100 can associate in the same complex and that TNF-alpha but not LTbeta signaling increases the association of p100 with RelB/p50 dimers in the nucleus, leading to the specific inhibition of RelB DNA binding. These results suggest that the alternative NF-kappaB pathway based on p100 processing may account not only for the activation of RelB/p52 dimers but also for that of RelB/p50 dimers and that p100 regulates the binding activity of RelB/p50 dimers via at least two distinct mechanisms depending on the signaling pathway involved.
Derudder
Emmanuel
E
Laboratoire Oncogenèse, Différenciation et Transduction du Signal, CNRS UPR 9079, Institut André Lwoff, 7 rue Guy Moquet, 94801 Villejuif, France.
Dejardin
Emmanuel
E
Pritchard
Linda L
LL
Green
Douglas R
DR
Korner
Marie
M
Baud
Veronique
V
D021581:Active Transport, Cell Nucleus; D000818:Animals; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D004720:Endonucleases; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D053259:Lymphotoxin beta Receptor; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism* / Q000502:physiology; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D020672:I-kappa B Proteins; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D018124:Receptors, Tumor Necrosis Factor; C497594:Relb protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051841:Transcription Factor RelB; D004247:DNA; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D004720:Endonucleases; C490640:Snd1 protein, mouse