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Molecules 2012, 17(10), 12365-12377; doi:10.3390/molecules171012365
Article

Phenylmethimazole Blocks dsRNA-Induced IRF3 Nuclear Translocation and Homodimerization

1, 1,2, 3,4, 1,3,5 and 1,3,5,6,7,*
1 Department of Specialty Medicine, Ohio University, Athens, OH 45701, USA 2 Interthyr Corporation, Athens, OH 45701, USA 3 Biomedical Engineering Program, Ohio University Russ College of Engineering & Technology, Ohio University, Athens, OH 45701, USA 4 Department of Chemical and Biomolecular Engineering, Ohio University Russ College of Engineering & Technology, Ohio University, Athens, OH 45701, USA 5 Diabetes Institute, Ohio University College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA 6 Department of Biological Sciences, Ohio University College of Arts & Sciences, Ohio University, Athens, OH 45701, USA 7 Molecular & Cellular Biology Program, Ohio University College of Arts & Sciences, Ohio University, Athens, OH 45701, USA
* Author to whom correspondence should be addressed.
Received: 5 October 2012 / Revised: 16 October 2012 / Accepted: 19 October 2012 / Published: 22 October 2012
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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.
Keywords: phenylmethimazole (C10); IRF3 phenylmethimazole (C10); IRF3
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).
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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.

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