Tautomycetin suppresses the TNFα/NF-κB pathway via inhibition of IKK activation

TNFα activated NF-κB and associated regulatory factors including IKK are strongly implicated in a variety of hematological and solid tumor malignancies. We show that tautomycetin (TC) specifically inhibits activation of NF-κB among the three TNFα effectors (NF-κB, JNK and caspase). TC inhibited T-loop phosphorylation of IKKα and IKKβ, thereby preventing degradation of the NF-κB inhibitor, IκBα. Co-immunoprecipitation experiments revealed that the catalytic subunit of PP1 (PP1C) was involved in the IKK complex. Pull-down analysis using recombinant GST-TNFα, showed that PP1C was recruited to TNFR1 together with IKK complex, RIP and TAK1 upon stimulus. These results suggest that the PP1 positively regulates the TNFα-induced NF-κB pathway at the level of IKK activation. Thus, TC might be used therapeutically to suppress the TNFα/NF-κB pathway.