TAB1: A Target of Triptolide in Macrophages

• TAB1 is identified and explored as the binding target of TP in macrophages
• TP inhibits TAK1 kinase activity by interfering with TAK1-TAB1 complex formation
• TP-TAB1 complex correlated with the inhibitory activity of TP against MAPK pathway
• Sequence between positions 373 and 502 of TAB1 was required for TP interaction

SummaryTriptolide (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.

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