Abstract: Previous studies revealed that phenylmethimazole (C10) inhibits IRF3 signaling, preventing dsRNA-induction of type 1 interferon gene expression, production, and downstream signaling. In the present study, we investigated the molecular basis for C10 inhibition of dsRNA-stimulated IRF3 signaling. IRF-3 Trans-AM assays were used to measure C10 effects on dsRNA induction of IRF3 DNA binding. Green fluorescent protein-labeled IRF3 was used to measure C10 effects on dsRNA-induced IRF3 nuclear translocation. Native PAGE, SDS PAGE, and western blotting were used to identify effects of C10 on IRF3 homodimer formation and phosphorylation, respectively. There was a significant impairment of dsRNA-induced IRF3 DNA binding activity in human embryonic kidney and pancreatic cancer cells with C10 treatment. C10 also blocked dsRNA-induced IRF3 nuclear translocation and homodimer formation without blocking serine 396 phosphorylation of IRF3. Together, these results indicate that C10 interferes with IRF3 signaling by blocking dsRNA-induced IRF3 homodimer formation, a prerequisite for nuclear translocation and DNA binding activities.
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Courreges, M.C.; Kantake, N.; Goetz, D.J.; Schwartz, F.L.; McCall, K.D. Phenylmethimazole Blocks dsRNA-Induced IRF3 Nuclear Translocation and Homodimerization. Molecules 2012, 17, 12365-12377.
Courreges MC, Kantake N, Goetz DJ, Schwartz FL, McCall KD. Phenylmethimazole Blocks dsRNA-Induced IRF3 Nuclear Translocation and Homodimerization. Molecules. 2012; 17(10):12365-12377.
Courreges, Maria C.; Kantake, Noriko; Goetz, Douglas J.; Schwartz, Frank L.; McCall, Kelly D. 2012. "Phenylmethimazole Blocks dsRNA-Induced IRF3 Nuclear Translocation and Homodimerization." Molecules 17, no. 10: 12365-12377.