Viral-Induced Alternative Splicing of Host Genes Promotes Influenza Replication

Thompson, M.; Dittmar, Mark; Mallory, Michael J.; Bhat, Prasanna; Ferretti, Max B; Fontoura, Beatriz M. A.; Cherry, Sara; Lynch, Kristen W.

doi:10.1101/2020.05.28.122044

Cited by 6 publications

(9 citation statements)

References 55 publications

(59 reference statements)

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“…Similar to our findings, little crossover between the set of genes showing differential splicing and differential expression was also observed in other systems [e.g. ( 36 , 37 )].…”

Section: Discussionsupporting

confidence: 92%

“…On the other hand, the transcription slowdown in IAV-infected cells ( 40 ) may contribute to the global increase in intron removal we observed and may overcome more subtle effects such as increased IR in a specific subset of mRNAs due to altered RED function. Interestingly, in a recent preprint by Thompson et al ., an approach similar to ours is used to assess to what extent hnRNP K could be mediating IAV-induced changes in ES events ( 37 ). The findings are similar to ours, i.e.…”

Section: Discussionmentioning

confidence: 99%

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Influenza virus infection induces widespread alterations of host cell splicing

Ashraf

Benoit‐Pilven

Ligneau

et al. 2020

NAR Genomics and Bioinformatics

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Influenza A viruses (IAVs) use diverse mechanisms to interfere with cellular gene expression. Although many RNA-seq studies have documented IAV-induced changes in host mRNA abundance, few were designed to allow an accurate quantification of changes in host mRNA splicing. Here, we show that IAV infection of human lung cells induces widespread alterations of cellular splicing, with an overall increase in exon inclusion and decrease in intron retention. Over half of the mRNAs that show differential splicing undergo no significant changes in abundance or in their 3′ end termination site, suggesting that IAVs can specifically manipulate cellular splicing. Among a randomly selected subset of 21 IAV-sensitive alternative splicing events, most are specific to IAV infection as they are not observed upon infection with VSV, induction of interferon expression or induction of an osmotic stress. Finally, the analysis of splicing changes in RED-depleted cells reveals a limited but significant overlap with the splicing changes in IAV-infected cells. This observation suggests that hijacking of RED by IAVs to promote splicing of the abundant viral NS1 mRNAs could partially divert RED from its target mRNAs. All our RNA-seq datasets and analyses are made accessible for browsing through a user-friendly Shiny interface (http://virhostnet.prabi.fr:3838/shinyapps/flu-splicing or https://github.com/cbenoitp/flu-splicing).

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“…Similar to our findings, little crossover between the set of genes showing differential splicing and differential expression was also observed in other systems [e.g. ( 36 , 37 )].…”

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Influenza virus infection induces widespread alterations of host cell splicing

Ashraf

Benoit‐Pilven

Ligneau

et al. 2020

NAR Genomics and Bioinformatics

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“…In all cases, the predominant splicing pattern observed upon T cell stimulation was differential inclusion of a cassette exons, as has typically been observed in other studies of signal-induced splicing regulation (Ajith et al, 2016;Thompson et al, 2020) (Supplemental Figure S1F,G).…”

Section: Temporal Regulation Of Alternative Splicing In Primary Human...supporting

confidence: 77%

Alternative Splicing of Apoptosis Genes Promotes Human T Cell Survival

Blake

Radens

Ferretti

et al. 2022

Preprint

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Alternative splicing occurs in the vast majority of human genes, giving rise to distinct mRNA and protein isoforms. We, and others, have previously identified hundreds of genes that change their isoform expression upon T cell activation via alternative splicing; however, how these changes link activation input with functional output remains largely unknown. Here we investigate how costimulation of T cells through the CD28 receptor impacts alternative splicing in T cells activated through the T cell receptor (CD3) and find that while CD28 signaling alone has minimal impact on splicing, it enhances the extent of change for up to 20% of TCR-induced alternative splicing events. Interestingly, a set of CD28-enhanced splicing events occur within genes encoding key components of the apoptotic signaling pathway; namely caspase-9, Bax and Bim. Using both CRISPR-edited cells and antisense oligos to force expression of specific isoforms, we show for all three of these genes that the isoform induced by CD3/CD28 costimulation promotes resistance to apoptosis, and that changes in all three genes together function combinatorially to further promote cell viability. Finally, we show that the JNK signaling pathway, induced downstream of CD3/CD28 costimulation, is required for each of these splicing events, further highlighting their co-regulation. Together these findings demonstrate that alternative splicing is a key mechanism by which costimulation of CD28 promotes viability of activated T cells.

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“…Others, including SFPQ, DDX5, EWSR1, HNRNPK, ADAR, PA2G4 were previously reported to promote replication of other RNA viruses (Garcia-Moreno et al, 2019;Gélinas et al, 2011;Landeras-Bueno et al, 2011;Li et al, 2013;Oakland et al, 2013;Thompson et al, 2020;Zhou et al, 2019a), supporting the role of these RBPs in SARS-CoV-2 replication. Interestingly, ILF3 was shown to participate to antiviral type I interferon response by promoting the expression of IFNB1 and interferon-stimulated gene (ISG) during host translational shutoff (Watson et al, 2020).…”

Section: Functional Interrogation Of the Sars-cov-2 Rbp Identified In Our Chirp-m/s Approachmentioning

confidence: 76%

Characterization and functional interrogation of SARS-CoV-2 RNA interactome

Labeau

Lefèvre‐Utile

Bonnet-Madin

et al. 2021

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19 pandemic, which has caused a devastating global health crisis. The emergence of highly transmissible novel viral strains that escape neutralizing responses emphasizes the urgent need to deepen our understanding of SARS-CoV-2 biology and to develop additional therapeutic strategies. Using a comprehensive identification of RNA binding proteins (RBP) by mass spectrometry (ChIRP-M/S) approach, we identified 142 high-confidence cellular factors that bind the SARS-CoV-2 viral genome during infection. By systematically knocking down their expression in a human lung epithelial cell line, we found that the majority of the RBPs identified in our study are proviral factors that regulate SARS-CoV-2 genome replication. We showed that some of these proteins represented drug targets of interest for inhibiting SARS-CoV-2 infection. In conclusion, this study provides a comprehensive view of the SARS-CoV-2 RNA interactome during infection and highlights candidates for host-centered antiviral therapies.

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Viral-Induced Alternative Splicing of Host Genes Promotes Influenza Replication

Cited by 6 publications

References 55 publications

Influenza virus infection induces widespread alterations of host cell splicing

Influenza virus infection induces widespread alterations of host cell splicing

Alternative Splicing of Apoptosis Genes Promotes Human T Cell Survival

Characterization and functional interrogation of SARS-CoV-2 RNA interactome

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