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J. Virol. doi:10.1128/JVI.00344-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Epstein-Barr virus SM protein functions as an alternative splicing factor

UF Shands Cancer Center, and Division of Infectious Diseases, Department of Medicine and Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL 32610

^* To whom correspondence should be addressed. Email: sswamina{at}ufl.edu.

	Abstract

Alternative splicing of RNA increases the coding potential of the genome and allows for additional regulatory control over gene expression. The full extent of alternative splicing remains to be defined but is likely to significantly expand the size of the human transcriptome. There are several examples of mammalian viruses regulating viral splicing or inhibiting cellular splicing in order to facilitate viral replication. Here we describe a viral protein which induces alternative splicing of a cellular RNA transcript. Epstein Barr virus SM protein is a viral protein essential for replication that enhances EBV gene expression by enhancing RNA stability and export. SM also increases cellular STAT1 expression, a central mediator of interferon signal transduction, but disproportionately increases the abundance of the STAT1 splicing isoform, which can act as a dominant-negative suppressor of STAT1. SM induces splicing of STAT1 at a novel 5' splice site, resulting in a STAT1 mRNA incapable of producing STAT1. SM-induced alternative splicing is dependent on the presence of an RNA sequence to which SM binds directly and which can confer SM-dependent splicing on heterologous RNA. The cellular splicing factor ASF/SF2 also binds to this region and inhibits SM-RNA binding and SM-induced alternative splicing. These results suggest that viruses may regulate cellular gene expression at the level of alternative mRNA splicing in order to facilitate virus replication or persistence in vivo.