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The ‘classical’ NF-κB activation pathway proceeds via IκB kinase (IKK)-β/γ-mediated phosphorylation, induced ubiquitination and the degradation of small IκBs. An alternative, NF-κB-inducing kinase and IKK-α-dependent pathway, which stimulates the processing of NF-κB2/p100, has recently been suggested. However, no physiological stimulus has been shown to trigger the activation of this pathway. Here we demonstrate that persistent stimulation with lymphotoxin β (LT-β) receptor agonists or lipopolysaccharide (LPS), but not with interleukin-1β, tumour necrosis factor-α or 12-O-tetradecanoylphorbol-13-acetate, induces the generation of p52 DNA-binding complexes by activating the processing of the p100 precursor. Induction of p52 DNA-binding activity is delayed in comparison with p50/p65 complexes and depends on de novo protein synthesis. p100 is constitutively and inducibly polyubiquitinated, and both ubiquitination and p52 generation are coupled to continuing p100 translation. Thus, both LT-β receptor agonists and LPS induce NF-κB/p100 processing to p52 at the level of the ribosome.