Abstract
Triptolide (TP) is a biologically active diterpene triepoxide from the Chinese herb Tripterygium wilfordii Hook f. Here, we identify and explore TAB1 as the binding target of TP in macrophages by using a comprehensive approach combining pull-down assays, in vitro assessments, and pharmaceutical and biological evaluation. We discover that TP inhibits TAK1 kinase activity by interfering with the formation of the TAK1-TAB1 complex, and the binding affinity of TP to TAB1 correlates highly with the inhibitory activity of TP against MAPK pathway activation in macrophages. We also find that the amino acid sequence between positions 373 and 502 of TAB1 is required for TP interaction. Our results suggest that TP could be a selective small-molecule inhibitor of the TAK1-TAB1 complex and that TAB1 could be a potential therapeutic target in inflammatory disease.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Cell Line
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Cytokines / genetics
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Cytokines / metabolism
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Diterpenes / chemistry
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Diterpenes / metabolism*
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Diterpenes / pharmacology
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Epoxy Compounds / chemistry
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Epoxy Compounds / metabolism
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Epoxy Compounds / pharmacology
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Inflammation / metabolism
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Lipopolysaccharides / toxicity
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Macrophages / drug effects
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Macrophages / metabolism*
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Mice
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Phenanthrenes / chemistry
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Phenanthrenes / metabolism*
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Phenanthrenes / pharmacology
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Protein Binding
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Tripterygium / chemistry
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Tripterygium / metabolism
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Adaptor Proteins, Signal Transducing
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Cytokines
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Diterpenes
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Epoxy Compounds
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Lipopolysaccharides
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Phenanthrenes
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Recombinant Proteins
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Tab1 protein, mouse
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Tumor Necrosis Factor-alpha
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triptolide