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

EMBO Rep. 2003 Jan;4(1):82-7. doi: 10.1038/sj.embor.embor710.

Abstract

The 'classical' NF-kappaB activation pathway proceeds via IkappaB kinase (IKK)-beta/gamma-mediated phosphorylation, induced ubiquitination and the degradation of small IkappaBs. An alternative, NF-kappaB-inducing kinase and IKK-alpha-dependent pathway, which stimulates the processing of NF-kappaB2/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-1beta, 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-kappaB/p100 processing to p52 at the level of the ribosome.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adenocarcinoma / pathology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • Breast Neoplasms / pathology
  • DNA / metabolism
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Enzyme Activation
  • Female
  • HeLa Cells / drug effects
  • HeLa Cells / metabolism
  • Humans
  • I-kappa B Proteins / chemistry
  • I-kappa B Proteins / genetics
  • I-kappa B Proteins / physiology
  • Interleukin-1 / pharmacology
  • Lipopolysaccharides / pharmacology*
  • Lymphotoxin beta Receptor
  • Lymphotoxin-alpha / agonists
  • Lymphotoxin-alpha / pharmacology*
  • Lymphotoxin-beta
  • Membrane Proteins / agonists
  • Membrane Proteins / pharmacology*
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / metabolism*
  • NF-kappa B p52 Subunit
  • Protein Binding / drug effects
  • Protein Precursors / metabolism*
  • Protein Processing, Post-Translational
  • Receptors, Tumor Necrosis Factor / agonists*
  • Receptors, Tumor Necrosis Factor / physiology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / physiology
  • Ribosomes / metabolism
  • Sequence Deletion
  • Tetradecanoylphorbol Acetate / pharmacology
  • Trans-Activators / metabolism*
  • Transcription Factors
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Necrosis Factor Ligand Superfamily Member 14
  • Tumor Necrosis Factor-alpha / pharmacology
  • Ubiquitin / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • I-kappa B Proteins
  • Interleukin-1
  • LTB protein, human
  • LTBR protein, human
  • Lipopolysaccharides
  • Lymphotoxin beta Receptor
  • Lymphotoxin-alpha
  • Lymphotoxin-beta
  • Membrane Proteins
  • NF-kappa B
  • NF-kappa B p52 Subunit
  • NFKBIA protein, human
  • PSIP1 protein, human
  • Protein Precursors
  • Receptors, Tumor Necrosis Factor
  • Recombinant Fusion Proteins
  • TNFSF14 protein, human
  • Trans-Activators
  • Transcription Factors
  • Tumor Necrosis Factor Ligand Superfamily Member 14
  • Tumor Necrosis Factor-alpha
  • Ubiquitin
  • NF-KappaB Inhibitor alpha
  • DNA
  • Tetradecanoylphorbol Acetate