The Splicing Factor Proline-Glutamine Rich (SFPQ/PSF) Is Involved in Influenza Virus Transcription

Landeras-Bueno, Sara; Jorba, Núria; Pérez-Cidoncha, Maite; Ortı́n, Juan

doi:10.1371/journal.ppat.1002397

Cited by 74 publications

(62 citation statements)

References 77 publications

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“…Furthermore, cyclin T1/CDK9 is proposed to recruit vRNP to hyperphosphorylated Pol II for cap snatching and to facilitate viral mRNA transcription (29). Additionally, splicing factor proline-glutamine rich (SFPQ/PSF) has been found to increase the efficiency of viral mRNA polyadenylation (30). In this study, we identified RRP1B as another important host factor for influenza virus transcription.…”

Section: Discussionmentioning

confidence: 86%

A Nucleolar Protein, Ribosomal RNA Processing 1 Homolog B (RRP1B), Enhances the Recruitment of Cellular mRNA in Influenza Virus Transcription

Hsu

Lee

et al. 2015

J Virol

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Influenza A virus (IAV) undergoes RNA transcription by a unique capped-mRNA-dependent transcription, which is carried out by the viral RNA-dependent RNA polymerase (RdRp), consisting of the viral PA, PB1, and PB2 proteins. However, how the viral RdRp utilizes cellular factors for virus transcription is not clear. Previously, we conducted a genome-wide pooled short hairpin RNA (shRNA) screen to identify host factors important for influenza A virus replication. Ribosomal RNA processing 1 homolog B (RRP1B) was identified as one of the candidates. RRP1B is a nucleolar protein involved in ribosomal biogenesis. Upon IAV infection, part of RRP1B was translocated from the nucleolus to the nucleoplasm, where viral RNA synthesis likely takes place. The depletion of RRP1B significantly reduced IAV mRNA transcription in a minireplicon assay and in virus-infected cells. Furthermore, we showed that RRP1B interacted with PB1 and PB2 of the RdRp and formed a coimmunoprecipitable complex with RdRp. The depletion of RRP1B reduced the amount of capped mRNA in the RdRp complex. Taken together, these findings indicate that RRP1B is a host factor essential for IAV transcription and provide a target for new antivirals. IMPORTANCEInfluenza virus is an important human pathogen that causes significant morbidity and mortality and threatens the human population with epidemics and pandemics every year. Due to the high mutation rate of the virus, antiviral drugs targeting viral proteins might ultimately lose their effectiveness. An alternative strategy that explores the genetic stability of host factors indispensable for influenza virus replication would thus be desirable. Here, we characterized the rRNA processing 1 homolog B (RRP1B) protein as an important cellular factor for influenza A virus transcription. We showed that silencing RRP1B hampered viral RNA-dependent RNA polymerase (RdRp) activity, which is responsible for virus transcription and replication. Furthermore, we reported that RRP1B is crucial for RdRp binding to cellular capped mRNA, which is a critical step of virus transcription. Our study not only provides a deeper understanding of influenza virus-host interplay, but also suggests a potential target for antiviral drug development.

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Section: Discussionmentioning

confidence: 86%

A Nucleolar Protein, Ribosomal RNA Processing 1 Homolog B (RRP1B), Enhances the Recruitment of Cellular mRNA in Influenza Virus Transcription

Hsu

Lee

et al. 2015

J Virol

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“…In agreement with this transcriptional association, interaction of the viral polymerase with host cell transcription-related factors has been reported, among which the interaction with the largest subunit of the RNAP II (11) should be emphasized. Other transcription-related factors found to interact with the viral polymerase are Erb-B3 binding protein 1 (Ebp-1) (12), which represses transcription of cell cycle genes regulated by E2F transcription factors (13); DDX5 protein (14), a transcription coactivator that may play a role in transcription initiation (15); SFPQ/PSF factor (14), which stimulates pre-mRNA processing (16) and is essential for influenza virus transcription increasing the efficiency of viral mRNA polyadenylation (17); and hCLE, a positive modulator of the RNAP II (18,19) which is required for influenza virus replication (20).…”

mentioning

confidence: 99%

CHD6, a Cellular Repressor of Influenza Virus Replication, Is Degraded in Human Alveolar Epithelial Cells and Mice Lungs during Infection

Alfonso

Rodríguez

Rodriguez

et al. 2013

J Virol

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The influenza virus polymerase associates to an important number of transcription-related proteins, including the largest subunit of the RNA polymerase II complex (RNAP II). Despite this association, degradation of the RNAP II takes place in the infected cells once viral transcription is completed. We have previously shown that the chromatin remodeler CHD6 protein interacts with the influenza virus polymerase complex, represses viral replication, and relocalizes to inactive chromatin during influenza virus infection. In this paper, we report that CHD6 acts as a negative modulator of the influenza virus polymerase activity and is also subjected to degradation through a process that includes the following characteristics: (i) the cellular proteasome is not implicated, (ii) the sole expression of the three viral polymerase subunits from its cloned cDNAs is sufficient to induce proteolysis, and (iii) degradation is also observed in vivo in lungs of infected mice and correlates with the increase of viral titers in the lungs. Collectively, the data indicate that CHD6 degradation is a general effect exerted by influenza A viruses and suggest that this viral repressor may play an important inhibitory role since degradation and accumulation into inactive chromatin occur during the infection. The influenza virus contains a segmented genome of eight negative-sense and single-stranded RNA molecules, whose expression takes place in the nucleus of the infected cell. Genomic RNAs (vRNAs) form ribonucleoprotein complexes (vRNPs) that are constituted by the three subunits of the polymerase (PB1, PB2, and PA) and the nucleoprotein (NP), which are responsible for genome expression (1-5). For viral replication, the vRNAs are copied to form full-length positive-stranded RNAs (cRNAs), which serve as templates for vRNA synthesis. During transcription, capped and polyadenylated viral mRNAs are synthesized by the viral polymerase. The mRNA synthesis is primed by shortcapped oligonucleotides of around 10 to 12 nucleotides scavenged from de novo synthesized host cell pre-mRNAs by a viral endonuclease activity (6). This transcription strategy involves a functional coupling between viral and cellular transcription for the capsnatching process, but this functional association is broader and applies to different steps of viral mRNA metabolism. Indeed, two of the viral transcripts are spliced (7,8), but the influenza virus does not possess a viral splicing system, since it is dependent on the host splicing machinery (9), an activity related to the RNA polymerase II (RNAP II) transcription. Furthermore, the influenza virus uses the mRNA export machinery of the infected cell at least for some of its mRNAs, and an active RNA polymerase II is required to facilitate nuclear export of selected viral mRNAs (10). In agreement with this transcriptional association, interaction of the viral polymerase with host cell transcription-related factors has been reported, among which the interaction with the largest subunit of the RNAP II (11) should be emphasi...

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“…Additionally, the most significantly enriched functional category in the emerging concepts was uniquely identified by INCATome ("Viral life cycle"). Several lines of evidence have been reported linking PSF and viral replication, gene expression, and reproductivity of HIV, influenza, and hepatitis delta viruses (Zolotukhin et al 2003;Greco-Stewart et al 2006;Landeras-Bueno et al 2011;Kula et al 2013). Finally, albeit INCATome yielded only four novel concepts, these have the specificity of not representing either responses to stimulus or developmental processes unlike all other novel concepts identified.…”

Section: New Biological Inferences Discovered With Incatomementioning

confidence: 98%

An improved analysis methodology for translational profiling by microarray

Sbarrato¹,

Spriggs²,

Wilson³

et al. 2017

RNA

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Translational regulation plays a central role in the global gene expression of a cell, and detection of such regulation has allowed deciphering of critical biological mechanisms. Genome-wide studies of the regulation of translation (translatome) performed on microarrays represent a substantial proportion of studies, alongside with recent advances in deep-sequencing methods. However, there has been a lack of development in specific processing methodologies that deal with the distinct nature of translatome array data. In this study, we confirm that polysome profiling yields skewed data and thus violates the conventional transcriptome analysis assumptions. Using a comprehensive simulation of translatome array data varying the percentage and symmetry of deregulation, we show that conventional analysis methods (Quantile and LOESS normalizations) and statistical tests failed, respectively, to correctly normalize the data and to identify correctly deregulated genes (DEGs). We thus propose a novel analysis methodology available as a CRAN package; Internal Control Analysis of Translatome (INCATome) based on a normalization tied to a group of invariant controls. We confirm that INCATome outperforms the other normalization methods and allows a stringent identification of DEGs. More importantly, INCATome implementation on a biological translatome data set (cells silenced for splicing factor PSF) resulted in the best normalization performance and an improved validation concordance for identification of true positive DEGs. Finally, we provide evidence that INCATome is able to infer novel biological pathways with superior discovery potential, thus confirming the benefits for researchers of implementing INCATome for future translatome studies as well as for existing data sets to generate novel avenues for research.

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The Splicing Factor Proline-Glutamine Rich (SFPQ/PSF) Is Involved in Influenza Virus Transcription

Cited by 74 publications

References 77 publications

A Nucleolar Protein, Ribosomal RNA Processing 1 Homolog B (RRP1B), Enhances the Recruitment of Cellular mRNA in Influenza Virus Transcription

A Nucleolar Protein, Ribosomal RNA Processing 1 Homolog B (RRP1B), Enhances the Recruitment of Cellular mRNA in Influenza Virus Transcription

CHD6, a Cellular Repressor of Influenza Virus Replication, Is Degraded in Human Alveolar Epithelial Cells and Mice Lungs during Infection

An improved analysis methodology for translational profiling by microarray

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