Influenza Viruses and mRNA Splicing: Doing More with Less

Dubois, Julia; Terrier, B.; Rosa‐Calatrava, Manuel

doi:10.1128/mbio.00070-14

Cited by 130 publications

(136 citation statements)

References 105 publications

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“…However, splicing sites cannot be assigned merely on the basis of splicing site scores, because we do not really know how the cellular splicing machinery is regulated during the selection of splicing sites (26). Furthermore, splicing during a viral infection is modulated by viral proteins, such as NS1 (27,54). Therefore, further studies are needed to confirm whether other novel viral proteins, some of which might not be functional, are expressed from these deduced spliced mRNAs.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, all immature mRNAs always have the potential to be edited by splicing. Yet only the M and NS segments are known to encode viral proteins in spliced mRNAs (27). In the present study, we focused on the PB2 segment, which is one of the longest segments of influenza A virus, to explore whether a novel spliced mRNA from the PB2 segment encodes a novel viral protein.…”

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confidence: 99%

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Identification of a Novel Viral Protein Expressed from the PB2 Segment of Influenza A Virus

Yamayoshi

Watanabe

Goto

et al. 2016

J Virol

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Over the past 2 decades, several novel influenza virus proteins have been identified that modulate viral infections in vitro and/or in vivo. The PB2 segment, which is one of the longest influenza A virus segments, is known to encode only one viral protein, PB2. In the present study, we used reverse transcription-PCR (RT-PCR) targeting viral mRNAs transcribed from the PB2 segment to look for novel viral proteins encoded by spliced mRNAs. We identified a new viral protein, PB2-S1, encoded by a novel spliced mRNA in which the region corresponding to nucleotides 1513 to 1894 of the PB2 mRNA is deleted. PB2-S1 was detected in virusinfected cells and in cells transfected with a protein expression plasmid encoding PB2. PB2-S1 localized to mitochondria, inhibited the RIG-I-dependent interferon signaling pathway, and interfered with viral polymerase activity (dependent on its PB1-binding capability). The nucleotide sequences around the splicing donor and acceptor sites for PB2-S1 were highly conserved among pre-2009 human H1N1 viruses but not among human H1N1pdm and H3N2 viruses. PB2-S1-deficient viruses, however, showed growth kinetics in MDCK cells and virulence in mice similar to those of wild-type virus. The biological significance of PB2-S1 to the replication and pathogenicity of seasonal H1N1 influenza A viruses warrants further investigation. IMPORTANCE Transcriptome analysis of cells infected with influenza

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Identification of a Novel Viral Protein Expressed from the PB2 Segment of Influenza A Virus

Yamayoshi

Watanabe

Goto

et al. 2016

J Virol

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“…Multiple viruses regulate the cell splicing machinery to generate alternative viral RNA products. Several RNA viruses (35)(36)(37)(38) and DNA viruses (39) use extensive alternative splicing of their mRNAs. The influenza A virus NS1 protein disorganizes nuclear speckles and Cajal bodies and binds members of the snRNP family of splicing factors and proteins required for 3=-terminal polyadenylation of host transcripts to facilitate splicing of viral RNAs (35).…”

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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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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“…Each ssRNA segment encodes at least one protein. 6 For almost three decades after the genome of influenza A viruses was first mapped, the genome of influenza A viruses was thought to encode 10 proteins. However, new findings have revealed that this eight-segment genome could encode up to 18 proteins, and more proteins could be discovered in the future.…”

Section: Introductionmentioning

confidence: 99%

Treatment of Influenza: Prospects of Post-Transcriptional Gene Silencing Through Synthetic siRNAs

Adeola¹

2017

Exploratory Research and Hypothesis in Medicine

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Influenza continues to pose significant threats to global health. The disease remains life-threatening, especially in children, the elderly and immunocompromised patients. High mutation rate and genetic reassortment enhance antigenic diversity and generation of novel strains. These, and other related factors, have made influenza viruses more resistant to control strategies and have necessitated the need for development of novel and effective strategies for prevention and treatment of influenza. While vaccination is the preferred method for prevention of influenza virus infections, preparation of influenza vaccines has to be carried out annually, and this takes several months. Anti-influenza drugs would, therefore, be the most immediate resource for combating newly emerging influenza viruses, especially if available vaccines proved ineffective. This review discusses the prospects of using small interfering RNAs (siRNAs) for treatment of influenza. Challenges associated with anti-influenza RNA interference (RNAi) and future directions are also highlighted

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Influenza Viruses and mRNA Splicing: Doing More with Less

Cited by 130 publications

References 105 publications

Identification of a Novel Viral Protein Expressed from the PB2 Segment of Influenza A Virus

Identification of a Novel Viral Protein Expressed from the PB2 Segment of Influenza A Virus

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

Treatment of Influenza: Prospects of Post-Transcriptional Gene Silencing Through Synthetic siRNAs

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