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Journal of Virology, April 2007, p. 3087-3096, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02032-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Classical Swine Fever Virus N^pro Interacts with Interferon Regulatory Factor 3 and Induces Its Proteasomal Degradation

Institute of Virology and Immunoprophylaxis, Mittelhäusern, Switzerland,¹ Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Sapporo, Japan²

Received 17 September 2006/ Accepted 29 December 2006

Viruses have evolved a multitude of strategies to subvert the innate immune system by interfering with components of the alpha/beta interferon (IFN-/ß) induction and signaling pathway. It is well established that the pestiviruses prevent IFN-/ß induction in their primary target cells, such as epitheloidal and endothelial cells, macrophages, and conventional dendritic cells, a phenotype mediated by the viral protein N^pro. Central players in the IFN-/ß induction cascade are interferon regulatory factor 3 (IRF3) and IRF7. Recently, it was proposed that classical swine fever virus (CSFV), the porcine pestivirus, induced the loss of IRF3 by inhibiting the transcription of IRF3 mRNA. In the present study, we show that endogenous IRF3 and IRF3 expressed from a cytomegalovirus (CMV) promoter are depleted in the presence of CSFV by means of N^pro, while CSFV does not inhibit CMV promoter-driven protein expression. We also demonstrate that CSFV does not reduce the transcriptional activity of the IRF3 promoter and does not affect the stability of IRF3 mRNA. In fact, CSFV N^pro induces proteasomal degradation of IRF3, as demonstrated by proteasome inhibition studies. Furthermore, N^pro coprecipitates with IRF3, suggesting that the proteasomal degradation of IRF3 is induced by a direct or indirect interaction with N^pro. Finally, we show that N^pro does not downregulate IRF7 expression.

Published ahead of print on 10 January 2007.

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