Lymphotoxin and lipopolysaccharide induce NF-kappaB-p52 generation by a co-translational mechanism.
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.
Mordmüller
Benjamin
B
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
Krappmann
Daniel
D
Esen
Meral
M
Wegener
Elmar
E
Scheidereit
Claus
C
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000473:pathology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000473:pathology; D004247:DNA / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha / Q000819:agonists / Q000494:pharmacology*; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000819:agonists / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit; D011485:Protein Binding / Q000187:drug effects; D011498:Protein Precursors / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D012270:Ribosomes / Q000378:metabolism; D017384:Sequence Deletion; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D020672:I-kappa B Proteins; D007375:Interleukin-1; C505886:LTB protein, human; C505697:LTBR protein, human; D008070:Lipopolysaccharides; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; C000606204:NFKBIA protein, human; C504649:PSIP1 protein, human; D011498:Protein Precursors; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C505914:TNFSF14 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; D013755:Tetradecanoylphorbol Acetate