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Journal of Virology, April 2007, p. 4255-4263, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.01930-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

The Nucleocytoplasmic Rabies Virus P Protein Counteracts Interferon Signaling by Inhibiting both Nuclear Accumulation and DNA Binding of STAT1{triangledown}

Aurore Vidy,1,{dagger} Jamila El Bougrini,2,{dagger} Mounira K. Chelbi-Alix,2 and Danielle Blondel1*

CNRS, UMR2472, IFR 115, and INRA, UMR1157, Virologie Moléculaire et Structurale, 91198 Gif sur Yvette, France,1 FRE 2944 CNRS, Institut Lwoff, 7 rue Guy Moquet, 94801 Villejuif, France2

Received 5 September 2006/ Accepted 29 January 2007

Rabies virus P protein inhibits alpha interferon (IFN-{alpha})- and IFN-{gamma}-stimulated Jak-STAT signaling by retaining phosphorylated STAT1 in the cytoplasm. Here, we show that P also blocks an intranuclear step that is the STAT1 binding to the DNA promoter of IFN-responsive genes. As P is a nucleocytoplasmic shuttling protein, we first investigated the effect of the cellular distribution of P on the localization of STAT1 and consequently on IFN signaling. We show that the localization of STAT1 is correlated with the localization of P: in cells expressing a nuclear form of P (the short P3 isoform or the complete P in the presence of the export inhibitor leptomycin B), STAT1 is nuclear, whereas in cells expressing a cytoplasmic form of P, STAT1 is cytoplasmic. However, the expression of nuclear forms of P inhibits the signaling of both IFN-{gamma} and IFN-{alpha}, demonstrating that the retention of STAT1 in the cytoplasm is not the only mechanism involved in the inhibition of IFN signaling. Electrophoretic mobility shift analysis indicates that P expression in the cell extracts of infected cells or in stable cell lines prevents IFN-induced DNA binding of STAT1. The loss of the DNA binding of STAT1 and ISGF3 was also observed when purified recombinant P or P3 was added to the extracts of IFN-{gamma}- or IFN-{alpha}-treated cells, indicating that P directly affects the DNA binding activity of STAT1. Then products of the rabies virus P gene are able to counteract IFN signaling by creating both cytoplasmic and nuclear blocks for STAT1.

* Corresponding author. Mailing address: Unité Mixte de Virologie Moléculaire et Structurale, UMR 2472, CNRS, 91198 Gif sur Yvette Cedex, France. Phone: 33-1-69 82 38 37. Fax: 33-1-69 82 43 08. E-mail: danielle.blondel{at}vms.cnrs-gif.fr

{triangledown} Published ahead of print on 7 February 2007.

{dagger} These authors contributed equally to this work.

Journal of Virology, April 2007, p. 4255-4263, Vol. 81, No. 8
0022-538X/07/$08.00+0     doi:10.1128/JVI.01930-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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