Abstract
Allantopyrone A is a fungal metabolite that uniquely possesses two α,β-unsaturated carbonyl moieties. We recently reported that allantopyrone A inhibited the nuclear factor-κB (NF-κB) signaling pathway induced by tumor necrosis factor (TNF)-α in human lung carcinoma A549 cells. In the present study, the mechanism by which allantopyrone A inhibits the TNF-α-induced signaling pathway was investigated in more detail. Allantopyrone A blocked extensive modifications to receptor-interacting protein 1 (RIP1) in the TNF receptor 1 (TNF-R1) complex. Allantopyrone A augmented the high-MW bands of TNF-R1, TNF receptor-associated factor 2, RIP1, the NF-κB subunit RelA and inhibitor of NF-κB kinase β in A549 cells, suggesting that it binds to and promotes the crosslinking of these proteins. The extracellular cysteine-rich domains of TNF-R1 were crosslinked by allantopyrone A more preferentially than its intracellular portion. The present results demonstrate that allantopyrone A interferes with multiple components of the TNF-R1 complex and blocks RIP1 modifications in the TNF-α-induced NF-κB signaling pathway.
MeSH terms
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A549 Cells
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Antibiotics, Antineoplastic / pharmacology*
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Cysteine / chemistry
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Cysteine / metabolism
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Genes, Reporter / drug effects
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HEK293 Cells
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / chemistry
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HSP90 Heat-Shock Proteins / genetics
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HSP90 Heat-Shock Proteins / metabolism
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Humans
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Molecular Weight
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NF-KappaB Inhibitor alpha / antagonists & inhibitors
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NF-KappaB Inhibitor alpha / chemistry
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NF-KappaB Inhibitor alpha / metabolism
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Peptide Fragments / antagonists & inhibitors
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Peptide Fragments / chemistry
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Protein Interaction Domains and Motifs
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Protein Multimerization / drug effects
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Protein Processing, Post-Translational / drug effects
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Pyrones / pharmacology*
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Receptor-Interacting Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Receptor-Interacting Protein Serine-Threonine Kinases / chemistry
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Receptor-Interacting Protein Serine-Threonine Kinases / genetics
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Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
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Receptors, Tumor Necrosis Factor, Type I / antagonists & inhibitors*
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Receptors, Tumor Necrosis Factor, Type I / chemistry
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Receptors, Tumor Necrosis Factor, Type I / genetics
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / drug effects*
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TNF Receptor-Associated Factor 2 / antagonists & inhibitors
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TNF Receptor-Associated Factor 2 / chemistry
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TNF Receptor-Associated Factor 2 / metabolism
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Transcription Factor RelA / antagonists & inhibitors
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Transcription Factor RelA / chemistry
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Transcription Factor RelA / metabolism
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / chemistry
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Antibiotics, Antineoplastic
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HSP90 Heat-Shock Proteins
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NFKBIA protein, human
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PSMD2 protein, human
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Peptide Fragments
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Pyrones
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RELA protein, human
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Receptors, Tumor Necrosis Factor, Type I
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Recombinant Fusion Proteins
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TNF Receptor-Associated Factor 2
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TNF protein, human
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TNFRSF1A protein, human
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TRAP1 protein, human
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha
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allantopyrone A
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NF-KappaB Inhibitor alpha
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RIPK1 protein, human
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Receptor-Interacting Protein Serine-Threonine Kinases
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Cysteine