A Cytoplasmic RNA Virus Alters the Function of the Cell Splicing Protein SRSF2

J Virol. 2017 Mar 13;91(7):e02488-16. doi: 10.1128/JVI.02488-16. Print 2017 Apr 1.

Abstract

To replicate efficiently, viruses must create favorable cell conditions and overcome cell antiviral responses. We previously reported that the reovirus protein μ2 from strain T1L, but not strain T3D, represses one antiviral response: alpha/beta interferon signaling. We report here that T1L, but not T3D, μ2 localizes to nuclear speckles, where it forms a complex with the mRNA splicing factor SRSF2 and alters its subnuclear localization. Reovirus replicates in cytoplasmic viral factories, and there is no evidence that reovirus genomic or messenger RNAs are spliced, suggesting that T1L μ2 might target splicing of cell RNAs. Indeed, RNA sequencing revealed that reovirus T1L, but not T3D, infection alters the splicing of transcripts for host genes involved in mRNA posttranscriptional modifications. Moreover, depletion of SRSF2 enhanced reovirus replication and cytopathic effect, suggesting that T1L μ2 modulation of splicing benefits the virus. This provides the first report of viral antagonism of the splicing factor SRSF2 and identifies the viral protein that determines strain-specific differences in cell RNA splicing.IMPORTANCE Efficient viral replication requires that the virus create favorable cell conditions. Many viruses accomplish this by repressing specific antiviral responses. We demonstrate here that some mammalian reoviruses, RNA viruses that replicate strictly in the cytoplasm, express a protein variant that localizes to nuclear speckles, where it targets a cell mRNA splicing factor. Infection with a reovirus strain that targets this splicing factor alters splicing of cell mRNAs involved in the maturation of many other cell mRNAs. Depletion of this cell splicing factor enhances reovirus replication and cytopathic effect. Our results provide the first evidence of viral antagonism of this splicing factor and suggest that downstream consequences to the cell are global and benefit the virus.

Keywords: RNA processing; SRSF; reovirus; splicing.

MeSH terms

  • Active Transport, Cell Nucleus
  • Amino Acid Sequence
  • Animals
  • Cell Nucleus / virology
  • Cytoplasm / virology
  • HEK293 Cells
  • Humans
  • Mice
  • Microtubules / metabolism
  • Orthoreovirus, Mammalian / physiology*
  • Protein Binding
  • Protein Multimerization
  • RNA Splicing
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Serine-Arginine Splicing Factors / physiology*
  • Viral Proteins / metabolism*
  • Virus Replication*

Substances

  • RNA, Messenger
  • SRSF2 protein, mouse
  • Viral Proteins
  • mu2 protein, Reovirus
  • Serine-Arginine Splicing Factors