Epoxyquinol B, a naturally occurring pentaketide dimer, inhibits NF-kappaB signaling by crosslinking TAK1

Several epoxyquinoids interfere with NF-kappaB signaling by targeting IKKbeta or NF-kappaB. We report that epoxyquinol B (EPQB), classified as an epoxyquiniod, inhibits NF-kappaB signaling through inhibition of the TAK1 complex, a factor upstream of IKKbeta and NF-kappaB. cDNA microarray analysis revealed that EPQB decreased TNF-alpha-induced expression of NF-kappaB target genes. EPQB covalently bound to a recombinant TAK1-TAB1 fusion protein in vitro, and inhibited its kinase activity. Furthermore, in vitro/in situ treatment with EPQB resulted in a ladder-like hypershift of TAK1 protein bands. We reported recently that EPQB crosslinks proteins via cysteine residues by opening its two epoxides, and our current results suggest that EPQB inhibits NF-kappaB signaling by crosslinking TAK1 itself or TAK1 through other proteins.