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.

1,25‐Dihydroxy‐vitamin D3 regulates NK‐cell cytotoxicity, cytokine secretion, and degranulation in women with recurrent pregnancy losses

“…Therefore, it seems that the LPS-induced TNF-α and IFN-γ production was suppressed by decreased phosphorylation of NFκB and 1,25(OH) 2 D 3 may block these signaling pathways. Recently, the anti-inflammatory effect of drug BAY 11-7082 was reported to be via suppression of the MyD88-dependent signaling network by targeting the ubiquitin system and not by inhibiting NF-κB [43]. Therefore, it may open a possibility that anti-inflammatory effect of 1,25(OH) 2 D 3 may be exerted through the suppression of MyD88-dependent signaling network.…”

Signal Inhibitory Receptor on Leukocytes-1 Limits the Formation of Neutrophil Extracellular Traps, but Preserves Intracellular Bacterial Killing

“…Celastrol and Bay 11-7082 are widely known for their potential to inhibit the transcription factor NF-kB (56,57). Both compounds, however, have been shown to directly or indirectly modulate numerous cellular targets, including JAK kinase, ERK, and JNK (58,59).…”

Targeting cytokine networks in KRAS-driven tumorigenesis

“…Yet the functional redundancy between IKKs such as TBK1 and IKKe, coupled with the reinforcing nature of this cytokine circuitry, suggests that lone inhibition of any one cytokine or kinase may be inadequate to disrupt signaling through this network. In this regard, drugs that suppress signaling more broadly by targeting IKK ubiquitination [18], or by inhibiting multiple kinases at once, may be more active than selective inhibitors. Indeed, BAY11-7082, which inhibits the E3 ligase linear ubiquitin assembly complex that activates both canonical and non-canonical IKKs [14,18], and momelotinib (previously known as CYT387), a multitargeted JAK/TBK1/ IKKe kinase inhibitor [10], are each potent suppressors of cytokine signaling and exhibit single agent activity in mouse models of Kras-driven lung cancer.…”

“…In this regard, drugs that suppress signaling more broadly by targeting IKK ubiquitination [18], or by inhibiting multiple kinases at once, may be more active than selective inhibitors. Indeed, BAY11-7082, which inhibits the E3 ligase linear ubiquitin assembly complex that activates both canonical and non-canonical IKKs [14,18], and momelotinib (previously known as CYT387), a multitargeted JAK/TBK1/ IKKe kinase inhibitor [10], are each potent suppressors of cytokine signaling and exhibit single agent activity in mouse models of Kras-driven lung cancer. Although treatment regimens that included either inhibitor resulted in robust activity and prolonged responses in aggressive Kras-p53 mutated murine lung cancer, resistance was found to emerge, highlighting further the ability of tumors to compensate through potential bypass pathways that reengage cytokine expression or render them cytokine-independent.…”