The Dengue Virus NS5 Protein Intrudes in the Cellular Spliceosome and Modulates Splicing

Maio, Federico A. De; Risso, Guillermo; Iglesias, Néstor Gabriel; Shah, Priya S.; Pozzi, Berta; Gebhard, Leopoldo Germán; Mammi, Pablo; Mancini, Estefanía; Yanovsky, Marcelo J.; Andino, Raul; Krogan, Nevan J.; Srebrow, Anabella; Gamarnik, Andrea V.

doi:10.1371/journal.ppat.1005841

Cited by 164 publications

(180 citation statements)

References 76 publications

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“…Notably, the EBV SM protein skews the mRNA splicing patterns of STAT1, enhancing production of the dominant-negative STAT1␤ isoform (55). Very recently, it has been shown that the NS5 protein of dengue virus binds to and interferes with components of the U5 snRNP particle and alters mRNA splicing of several antiviral factors (64). In contrast to our results for reovirus, dengue NS5 does not appear to affect the intranuclear localization of its splicing targets (64).…”

Section: Discussioncontrasting

confidence: 99%

“…Very recently, it has been shown that the NS5 protein of dengue virus binds to and interferes with components of the U5 snRNP particle and alters mRNA splicing of several antiviral factors (64). 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).…”

Section: Discussionmentioning

confidence: 99%

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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%

Section: Discussionmentioning

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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“…For example, NS4A was enriched for interaction partners involved in ER and Golgi function (Figure 1F), consistent with its localization ( Figures S2 and S3) and role in forming convoluted membranes in the ER (Miller et al, 2007). Furthermore, NS5 was enriched for interaction partners linked to nuclear functions including chromatin modification and RNA processing (Figure 1F), in line with its nuclear localization (Figure S2), and our recent finding that DENV NS5 inhibits splicing of host mRNA (De Maio et al, 2016). Our network is also enriched for interactions with proteins involved in lipid metabolism and ER stress, which could help elucidate the exact mechanisms of these previously known perturbations (Heaton and Randall, 2010; Pena and Harris, 2011).…”

Section: Resultssupporting

confidence: 81%

Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

Shah

Link

Jang

et al. 2018

Cell

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263

322

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Mosquito-borne flaviviruses, including dengue virus (DENV) and Zika virus (ZIKV), are a growing public health concern. Systems level analysis of how flaviviruses hijack cellular processes through virus-host protein-protein interactions (PPIs) provide information about their replication and pathogenic mechanisms. We used affinity purification-mass spectrometry (AP-MS) to compare flavivirus-host interactions for two viruses (DENV and ZIKV) in two hosts (human and mosquito). Conserved virus-host PPIs revealed that the flavivirus NS5 protein suppresses interferon stimulated genes by inhibiting recruitment of the transcription complex PAF1C, and that chemical modulation of SEC61 inhibits DENV and ZIKV replication in human and mosquito cells. Finally, we identified a ZIKV-specific interaction between NS4A and ANKLE2, a gene linked to hereditary microcephaly, and showed that ZIKV NS4A causes microcephaly in Drosophila in an ANKLE2-dependent manner. Thus, comparative flavivirus-host PPI mapping provides biological insights, and when coupled with in vivo models, can be used to unravel pathogenic mechanisms.

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“…336,337 Additionally, methods that map physical interactions between viral and host components (both RNA and proteins) have also greatly expanded our understanding of host factors. 338,339 …”

Section: Pro-viral Host Factorsmentioning

confidence: 99%

Biochemistry and Molecular Biology of Flaviviruses

et al. 2018

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Flaviviruses, such as dengue, Japanese encephalitis, tick-borne encephalitis, West Nile, yellow fever, and Zika viruses, are critically important human pathogens that sicken a staggeringly high number of humans every year. Most of these pathogens are transmitted by mosquitos, and not surprisingly, as the earth warms and human populations grow and move, their geographic reach is increasing. Flaviviruses are simple RNA–protein machines that carry out protein synthesis, genome replication, and virion packaging in close association with cellular lipid membranes. In this review, we examine the molecular biology of flaviviruses touching on the structure and function of viral components and how these interact with host factors. The latter are functionally divided into pro-viral and antiviral factors, both of which, not surprisingly, include many RNA binding proteins. In the interface between the virus and the hosts we highlight the role of a noncoding RNA produced by flaviviruses to impair antiviral host immune responses. Throughout the review, we highlight areas of intense investigation, or a need for it, and potential targets and tools to consider in the important battle against pathogenic flaviviruses.

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The Dengue Virus NS5 Protein Intrudes in the Cellular Spliceosome and Modulates Splicing

Cited by 164 publications

References 76 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

Comparative Flavivirus-Host Protein Interaction Mapping Reveals Mechanisms of Dengue and Zika Virus Pathogenesis

Biochemistry and Molecular Biology of Flaviviruses

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