Derudder Emmanuel, Dejardin Emmanuel, Pritchard Linda L, Green Douglas R, Korner Marie, Baud Veronique
Laboratoire Oncogenèse, Différenciation et Transduction du Signal, CNRS UPR 9079, Institut André Lwoff, 7 rue Guy Moquet, 94801 Villejuif, France.
J Biol Chem. 2003 Jun 27;278(26):23278-84. doi: 10.1074/jbc.M300106200. Epub 2003 Apr 21.
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.
肿瘤坏死因子-α（TNF-α）和淋巴毒素-β受体（LTβR）信号传导通过激活核因子-κB（NF-κB）在炎症和免疫反应中均发挥重要作用。利用各种缺陷型小鼠胚胎成纤维细胞，我们比较了响应TNF-α和LTβR激活而导致NF-κB诱导的信号通路。我们证明，LTβR连接不仅诱导RelA/p50二聚体，还诱导RelB/p50二聚体，而TNF-α仅诱导RelA/p50二聚体。LTβR诱导的RelB/p50结合需要由IKKα介导的p100加工，但独立于IKKβ、NEMO/IKKγ和RelA。此外，我们表明RelB、p50和p100可以在同一复合物中结合，并且TNF-α而非LTβ信号传导增加了p100与细胞核中RelB/p50二聚体的结合，导致RelB DNA结合的特异性抑制。这些结果表明，基于p100加工的替代NF-κB途径可能不仅解释了RelB/p52二聚体的激活，还解释了RelB/p50二聚体的激活，并且p100根据所涉及的信号通路通过至少两种不同机制调节RelB/p50二聚体的结合活性。
