Abstract
Alternative splicing (AS) is a central mechanism of genetic regulation which modifies the sequence of RNA transcripts in higher eukaryotes. AS has been shown to increase both the variability and diversity of the cellular proteome by changing the composition of resulting proteins through differential choice of exons to be included in mature mRNAs. In the present study, alterations to the global RNA splicing landscape of cellular genes upon viral infection were investigated using mammalian reovirus as a model. Our study provides the first comprehensive portrait of global changes in the RNA splicing signatures that occur in eukaryotic cells following infection with a human virus. We identify 240 modified alternative splicing events upon infection which belong to transcripts frequently involved in the regulation of gene expression and RNA metabolism. Using mass spectrometry, we also confirm modifications to transcript-specific peptides resulting from AS in virus-infected cells. These findings provide additional insights into the complexity of virus-host interactions as these splice variants expand proteome diversity and function during viral infection.
Highlights
Virus-host studies of a wide range of human viruses have identified many changes that occur in host cells upon viral infection, including modulation of host DNA/RNA/protein synthesis, induction of various anti-viral pathways, and sequestration/degradation of cellular proteins [1,2,3]
In order to capture Alternative splicing (AS) changes preceding the cytopathic effect, RNA sequencing (RNA-seq) was performed on infected cells at 14 hrs post-infection, and viral infection was confirmed by qRT-PCR using specific primers for three viral genes (Fig A in S1 Appendix)
In order to identify the cellular AS patterns that are altered during reovirus infection, we evaluated modification to discrete splicing region on isoforms by quantifying all alternative splicing events (ASEs) using the percent spliced-in (PSI) metric
Summary
Virus-host studies of a wide range of human viruses have identified many changes that occur in host cells upon viral infection, including modulation of host DNA/RNA/protein synthesis, induction of various anti-viral pathways, and sequestration/degradation of cellular proteins [1,2,3]. Viruses rely on host cell proteins and their associated mechanisms to replicate [4,5]. Numerous virus-host interactions occur during infection, which enable both partners to respond to each other. Identifying the modifications that result from virus-host interactions is currently a crucial frontier in understanding viral infection.
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