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J. Biol. Chem., Vol. 279, Issue 30, 31471-31477, July 23, 2004

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Inhibition of RNA Polymerase II Phosphorylation by a Viral Interferon Antagonist^*

Daniel Thomas, Gjon Blakqori, Valentina Wagner, Marius Banholzer, Nina Kessler, Richard M. Elliott, Otto Haller, and Friedemann Weber¶

From the Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, D-79008 Freiburg, Germany and the Division of Virology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G11 5JR, Scotland, United Kingdom

Many viruses subvert the cellular interferon (IFN) system with so-called IFN antagonists. Bunyamwera virus (BUNV) belongs to the family Bunyaviridae and is transmitted by arthropods. We have recently identified the nonstructural protein NSs of BUNV as a virulence factor that inhibits IFN- gene expression in the mammalian host. Here, we demonstrate that NSs targets the RNA polymerase II (RNAP II) complex. The C-terminal domain (CTD) of RNAP II consists of 52 repeats of the consensus sequence YSPTSPS. Phosphorylation at serine 5 is required for efficient initiation of transcription, and subsequent phosphorylation at serine 2 is required for mRNA elongation and 3'-end processing. In BUNV-infected mammalian cells, serine 5 phosphorylation occurred normally. Furthermore, RNAP II was able to bind to the IFN- gene promoter as revealed by chromatin immunoprecipitation analysis, indicating that the initiation of transcription was not disturbed by NSs. However, NSs prevented CTD phosphorylation at serine 2, suggesting a block in transition from initiation to elongation. Surprisingly, no interference with CTD phosphorylation was observed in insect cells. Our results indicate that BUNV uses an unconventional mechanism to block IFN synthesis in the mammalian host by directly dysregulating RNAP II. Moreover, by inducing a general transcriptional block, NSs may contribute to the lytic infection observed in mammalian cells as opposed to persistent infection in the insect host.

Received for publication, January 28, 2004 , and in revised form, May 7, 2004.

^* This work was supported by grants from the Deutsche Forschungsgemeinschaft (to F. W.) and the Wellcome Trust (to R. M. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 49-761-203-6614; Fax: 49-761-20-6562; E-mail: fweber{at}UKL.uni-freiburg.de.

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