The anti-inflammatory drug BAY 11-7082 suppresses the MyD88-dependent signalling network by targeting the ubiquitin system

Sam Strickson, David G Campbell, Christoph H Emmerich, Axel Knebel, Lorna Plater, Maria Stella Ritorto, Natalia Shpiro, Philip Cohen

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    112 Citations (Scopus)
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    Abstract

    The compound BAY 11-7082 inhibits I?Ba [inhibitor of NF-?B (nuclear factor ?B)a] phosphorylation in cells and has been used to implicate the canonical IKKs (I?B kinases) and NF-?B 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 HIF1a (hypoxia-inducible factor 1a) 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-?B.
    Original languageEnglish
    Pages (from-to)427-437
    Number of pages11
    JournalBiochemical Journal
    Volume451
    Issue number3
    DOIs
    Publication statusPublished - 1 May 2013

    Keywords

    • lymphoma
    • linear ubiquitin assembly complex (LUBAC)
    • myeloid differentiation factor 88 (MyD88)
    • nuclear factor κB (NF-κB)
    • proteasome
    • ubiquitin conjugating 13 (Ubc13)

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