title: The anti-inflammatory drug BAY 11-7082 suppresses the MyD88-dependent signalling network by targeting the ubiquitin system.
abstract: The compound BAY 11-7082 inhibits IκBα [inhibitor of NF-κB (nuclear factor κB)α] phosphorylation in cells and has been used to implicate the canonical IKKs (IκB kinases) and NF-κB in >350 publications. In the present study we report that BAY 11-7082 does not inhibit the IKKs, but suppresses their activation in LPS (lipopolysaccharide)-stimulated RAW macrophages and IL (interleukin)-1-stimulated IL-1R (IL-1 receptor) HEK (human embryonic kidney)-293 cells. BAY 11-7082 exerts these effects by inactivating the E2-conjugating enzymes Ubc (ubiquitin conjugating) 13 and UbcH7 and the E3 ligase LUBAC (linear ubiquitin assembly complex), thereby preventing the formation of Lys63-linked and linear polyubiquitin chains. BAY 11-7082 prevents ubiquitin conjugation to Ubc13 and UbcH7 by forming a covalent adduct with their reactive cysteine residues via Michael addition at the C3 atom of BAY 11-7082, followed by the release of 4-methylbenzene-sulfinic acid. BAY 11-7082 stimulated Lys48-linked polyubiquitin chain formation in cells and protected HIF1α (hypoxia-inducible factor 1α) from proteasomal degradation, suggesting that it inhibits the proteasome. The results of the present study indicate that the anti-inflammatory effects of BAY 11-7082, its ability to induce B-cell lymphoma and leukaemic T-cell death and to prevent the recruitment of proteins to sites of DNA damage are exerted via inhibition of components of the ubiquitin system and not by inhibiting NF-κB.
authors: MRC Protein Phosphorylation Unit, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, UK.
authors: Sam
authors: S
authors: Strickson
authors: David G
authors: DG
authors: Campbell
authors: Christoph H
authors: CH
authors: Emmerich
authors: Axel
authors: A
authors: Knebel
authors: Lorna
authors: L
authors: Plater
authors: Maria Stella
authors: MS
authors: Ritorto
authors: Natalia
authors: N
authors: Shpiro
authors: Philip
authors: P
authors: Cohen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013450:Sulfones / Q000494:pharmacology*; D025801:Ubiquitin / Q000037:antagonists & inhibitors / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020672:I-kappa B Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D009570:Nitriles; D017472:Receptors, Interleukin-1; D013450:Sulfones; D025801:Ubiquitin; D000072000:NF-KappaB Inhibitor alpha; C079437:UBE2L3 protein, human; C471607:UBE2N protein, human; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex