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.
Kamiyama
Hiroshi
H
Antibiotics Laboratory, RIKEN Advanced Science Institute, Wako, Saitama, Japan.
Usui
Takeo
T
Sakurai
Hiroaki
H
Shoji
Mitsuru
M
Hayashi
Yujiro
Y
Kakeya
Hideaki
H
Osada
Hiroyuki
H
D000893:Anti-Inflammatory Agents; D003432:Cross-Linking Reagents; D003545:Cysteine / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D000099151:MAP Kinase Kinase Kinase 7
D000893:Anti-Inflammatory Agents; D003432:Cross-Linking Reagents; D003545:Cysteine; D004852:Epoxy Compounds; D006873:Hydroquinones; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C469247:epoxyquinol B