Lymphotoxin and lipopolysaccharide induce NF-κB-p52 generation by a co-translational mechanism


  • B. Mordmueller
  • D. Krappmann
  • M. Esen
  • E. Wegener
  • C. Scheidereit


  • EMBO Reports


  • EMBO Rep 4 (1): 82-87


  • The 'classical' NF-{kappa}B activation pathway proceeds via IκB kinase (IKK)-{beta}/{gamma}-mediated phosphorylation, induced ubiquitination and the degradation of small I{kappa}Bs. An alternative, NF-{kappa}B-inducing kinase and IKK-{alpha}-dependent pathway, which stimulates the processing of NF-{kappa}B2/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 {beta} (LT-{beta}) receptor agonists or lipopolysaccharide (LPS), but not with interleukin-1{beta}, tumour necrosis factor-{alpha} 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-{beta} receptor agonists and LPS induce NF-{kappa}B/p100 processing to p52 at the level of the ribosome.