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The NPro Product of Bovine Viral Diarrhea Virus Inhibits DNA Binding by Interferon Regulatory Factor 3 and Targets It for Proteasomal Degradation

Louise Hilton,¹ Kartykayan Moganeradj,¹ Gang Zhang,² Yun-Hsiang Chen,³ Richard E. Randall,³ John W. McCauley,^2, and Stephen Goodbourn^1*

Division of Basic Medical Sciences, St. George's, University of London, London SW17 0RE, United Kingdom,¹ Institute for Animal Health, Compton Laboratory, Compton, Newbury, Berkshire RG20 7NN, United Kingdom,² Biomolecular Sciences Building, School of Biology, University of St. Andrew's, North Haugh, St. Andrews, KY16 9ST, United Kingdom³

Received 2 June 2006/ Accepted 4 September 2006

Bovine viral diarrhea virus (BVDV) is a pestivirus that can establish a persistent infection in the developing fetus and has the ability to disable the production of type I interferon. In this report, we extend our previous observations that BVDV encodes a protein able to specifically block the activity of interferon regulatory factor 3 (IRF-3), a transcription factor essential for interferon promoter activation, by demonstrating that this is a property of the N-terminal protease fragment (NPro) of the BVDV polyprotein. Although BVDV infections cause relocalization of cellular IRF-3 from the cytoplasm to the nucleus early in infection, NPro blocks IRF-3 from binding to DNA. NPro has the additional property of targeting IRF-3 for polyubiquitination and subsequent destruction by cellular multicatalytic proteasomes. The autoprotease activity of NPro is not required for the inhibition of type I interferon induction or the targeting of IRF-3 for degradation.

Published ahead of print on 13 September 2006.

Present address: Division of Virology, National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom.

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