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

The compound BAY 11-7082 inhibits IκBα phosphorylation in cells and has been used to implicate the canonical IκB kinases (IKKs) and NFκB in <350 publications. Here we report that BAY 11-7082 does not inhibit the IKKs but suppresses their activation in LPS-stimulated RAW macrophages and IL-1-stimulated IL-1R HEK293 cells. BAY 11-7082 exerts these effects by inactivating the E2 conjugating enzymes Ubc13 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-sulphinic 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. Our results 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 the ubiquitin system and not by inhibiting NFκB.
Source: BJ Signal - Category: Biochemistry Authors: Tags: BJ Signal Source Type: research