Global Profiling of the Cellular Alternative RNA Splicing Landscape during Virus-Host Interactions

Boudreault, Simon; Martenon-Brodeur, Camille; Caron, Marie; Garant, Jean-Michel; Tremblay, Marie-Pier; Armero, Victoria E. S.; Durand, Mathieu; Lapointe, Elvy; Thibault, Philippe; Tremblay-Létourneau, Maude; Perreault, Jean‐Pierre; Scott, Michelle S.; Lemay, Guy; Bisaillon, Martin

doi:10.1371/journal.pone.0161914

Cited by 57 publications

(57 citation statements)

References 82 publications

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“…In contrast to our results for reovirus, dengue NS5 does not appear to affect the intranuclear localization of its splicing targets (64). Finally, in a recent report reovirus T3D was shown to alter cell mRNA splicing, but the impact on viral replication and the underlying mechanism were not investigated (65). It is interesting that a single reovirus protein, 2, can modulate both IFN signaling (7) and SRSF2 function to benefit the virus.…”

Section: Discussioncontrasting

confidence: 99%

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

Rivera-Serrano

Fritch

Scholl

et al. 2017

J Virol

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To replicate efficiently, viruses must create favorable cell conditions and overcome cell antiviral responses. We previously reported that the reovirus protein 2 from strain T1L, but not strain T3D, represses one antiviral response: alpha/beta interferon signaling. We report here that T1L, but not T3D, 2 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 2 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 2 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 V iruses are obligatory intracellular pathogens that require a hospitable cell environment for their replication. However, viral infection induces cell innate responses that are antiviral. Accordingly, viruses have evolved numerous strategies to evade these responses. For example, viral infection of virtually any cell type induces a protective type I interferon (IFN-␣/␤) response, and many viruses use at least one mechanism to suppress this antiviral system (1, 2). Viral proteins that inhibit cell antiviral responses have been identified for most viruses, as have the cell proteins they target (1, 3). Not surprisingly, the most commonly identified targets are cell proteins involved in the IFN-␣/␤ response (1, 2).Mammalian reoviruses are double-stranded RNA nonenveloped viruses that replicate in membrane-associated cytoplasmic viral factories (VFs) (4, 5). Reovirus strain type 1 Lang (T1L) represses IFN-␤ signaling, while type 3 Dearing (T3D) does not (6), and this

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Section: Discussioncontrasting

confidence: 99%

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

Rivera-Serrano

Fritch

Scholl

et al. 2017

J Virol

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“…These observations are in agreement with a growing awareness that viral infection can not only alter gene expression but also lead to altered splicing patterns. Host splicing changes have been observed during infection with DNA viruses (HSV-1 (Hu et al, 2016), HCMV (Batra et al, 2016)) as well as RNA viruses such as reovirus (Boudreault et al, 2016), dengue virus (Sessions et al, 2013), and zika virus (Hu et al, 2017). However, these studies represent only the tip of the iceberg as they have mostly lacked the sequencing depth, and subsequent orthogonal validation, that is needed for a comprehensive quantitative analysis of host splicing (Mehmood et al, 2019; Shen et al, 2012)(Vaquero-Garcia et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Viral-Induced Alternative Splicing of Host Genes Promotes Influenza Replication

Thompson

Dittmar

Mallory

et al. 2020

Preprint

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Viral infection induces the expression of numerous host genes that impact the outcome of infection. Here we show that infection of human lung epithelial cells with Influenza A virus (IAV) also induces a broad program of alternative splicing of host genes. While these splicing-regulated genes are not enriched for canonical regulators of viral infection, we find that many of these genes do impact replication of IAV. Moreover, specific inhibition of the IAV-induced splicing in several cases also attenuates viral infection. We further show that approximately a quarter of the IAV-induced splicing events are regulated by hnRNP K, a host protein that required for efficient splicing of the IAV M transcript in nuclear speckles. Notably, we find that hnRNP K accumulates in nuclear speckles upon IAV infection, which is likely to alter the accessibility of hnRNP K for host transcripts thereby leading to a program of host splicing changes that promote IAV replication.

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“…In the case of HSV1 infection, nuclear RNA export was affected, and profound modifications of the splicing of cellular genes were observed (61). In the case of orthoreovirus, another double-stranded RNA (dsRNA) virus, infection perturbs RNA splicing (62,63), but PABPC localization has not been studied. Our observation that the splicing of the NCOA1 RNA is affected by rotavirus infection regardless of the ES phenotype might indicate that rotavirus infection is more perturbative for RNA splicing than reported here.…”

Section: Discussionmentioning

confidence: 99%

Rotavirus Infection Alters Splicing of the Stress-Related Transcription Factor XBP1

Duarte

Vende

Charpilienne

et al. 2019

J Virol

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XBP1 is a stress-regulated transcription factor also involved in mammalian host defenses and innate immune response. Our investigation of XBP1 RNA splicing during rotavirus infection revealed that an additional XBP1 RNA (XBP1es) that corresponded to exon skipping in the XBP1 pre-RNA is induced depending on the rotavirus strain used. We show that the translation product of XBP1es (XBP1es) has trans-activation properties similar to those of XBP1 on ER stress response element (ERSE) containing promoters. Using monoreassortant between ES+ (“skipping”) and ES– (“nonskipping”) strains of rotavirus, we show that gene 7 encoding the viral translation enhancer NSP3 is involved in this phenomenon and that exon skipping parallels the nuclear relocalization of cytoplasmic PABP. We further show, using recombinant rotaviruses carrying chimeric gene 7, that the ES+ phenotype is linked to the eIF4G-binding domain of NSP3. Because the XBP1 transcription factor is involved in stress and immunological responses, our results suggest an alternative way to activate XBP1 upon viral infection or nuclear localization of PABP. IMPORTANCE Rotavirus is one of the most important pathogens causing severe gastroenteritis in young children worldwide. Here we show that infection with several rotavirus strains induces an alternative splicing of the RNA encoding the stressed-induced transcription factor XBP1. The genetic determinant of XBP1 splicing is the viral RNA translation enhancer NSP3. Since XBP1 is involved in cellular stress and immune responses and since the XBP1 protein made from the alternatively spliced RNA is an active transcription factor, our observations raise the question of whether alternative splicing is a cellular response to rotavirus infection.

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Global Profiling of the Cellular Alternative RNA Splicing Landscape during Virus-Host Interactions

Cited by 57 publications

References 82 publications

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

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

Viral-Induced Alternative Splicing of Host Genes Promotes Influenza Replication

Rotavirus Infection Alters Splicing of the Stress-Related Transcription Factor XBP1

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