The non-structural NS1 protein of influenza viruses modulates TP53 splicing through the host factor CPSF4

Julia Dubois, Aurélien Traversier, Thomas Julien, Blandine Padey, Bruno Lina, Jean-Christophe Bourdon, Virginie Marcel, Guy Boivin, Manuel Rosa-Calatrava, Olivier Terrier (Lead / Corresponding author)

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Abstract

Influenza A viruses (IAV) are known to modulate and "hijack" several cellular host mechanisms, including gene splicing and RNA maturation machineries. These modulations alter host cellular responses and enable an optimal expression of viral products throughout infection. The interplay between the host protein p53 and IAV, in particular through the viral nonstructural protein NS1, has been shown to be supportive for IAV replication. However, it remains unknown whether alternatively spliced isoforms of p53, known to modulate p53 transcriptional activity, are affected by IAV infection and contribute to IAV replication. Using a TP53 minigene, which mimics intron 9 alternative splicing, we have shown here that the NS1 protein of IAV changes the expression pattern of p53 isoforms. Our results demonstrate that CPSF4 (cellular protein cleavage and polyadenylation specificity factor 4) independently and the interaction between NS1 and CPSF4 modulate the alternative splicing of TP53 transcripts, which may result in the differential activation of p53-responsive genes. Finally, we report that CPSF4 and most likely beta and gamma spliced p53 isoforms affect both viral replication and IAV-associated type I interferon secretion. All together, our data show that cellular p53 and CPSF4 factors, both interacting with viral NS1, have a crucial role during IAV replication that allows IAV to interact with and alter the expression of alternatively spliced p53 isoforms in order to regulate the cellular innate response, especially via type I interferon secretion, and perform efficient viral replication.IMPORTANCE Influenza A viruses (IAV) constitute a major public health issue, causing illness and death in high-risk populations during seasonal epidemics or pandemics. IAV are known to modulate cellular pathways to promote their replication and avoid immune restriction via the targeting of several cellular proteins. One of these proteins, p53, is a master regulator involved in a large panel of biological processes, including cell cycle arrest, apoptosis, or senescence. This "cellular gatekeeper" is also involved in the control of viral infections, and viruses have developed a wide diversity of mechanisms to modulate/hijack p53 functions to achieve an optimal replication in their hosts. Our group and others have previously shown that p53 activity is finely modulated by different multilevel mechanisms during IAV infection. Here, we characterized IAV nonstructural protein NS1 and the cellular factor CPSF4 as major partners involved in the IAV-induced modulation of the TP53 alternative splicing that was associated with a strong modulation of p53 activity and notably the p53-mediated antiviral response.

Original languageEnglish
Article numbere02168-18
Pages (from-to)1-19
Number of pages19
JournalJournal of Virology
Volume93
Issue number7
Early online date16 Jan 2019
DOIs
Publication statusPublished - Mar 2019

Fingerprint

Cleavage And Polyadenylation Specificity Factor
Integration Host Factors
Influenza A virus
Orthomyxoviridae
alternative splicing
proteins
virus replication
Protein Isoforms
Alternative Splicing
Proteins
Virus Diseases
Virus Replication
Interferon Type I
interferons
influenza virus INS1 protein
infection
Viral Nonstructural Proteins
RNA Splicing
Biological Phenomena
secretion

Keywords

  • CPSF30
  • antiviral response
  • influenza viruses
  • p53
  • splicing
  • virus-host interactions

Cite this

Dubois, Julia ; Traversier, Aurélien ; Julien, Thomas ; Padey, Blandine ; Lina, Bruno ; Bourdon, Jean-Christophe ; Marcel, Virginie ; Boivin, Guy ; Rosa-Calatrava, Manuel ; Terrier, Olivier. / The non-structural NS1 protein of influenza viruses modulates TP53 splicing through the host factor CPSF4. In: Journal of Virology. 2019 ; Vol. 93, No. 7. pp. 1-19.
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Dubois, J, Traversier, A, Julien, T, Padey, B, Lina, B, Bourdon, J-C, Marcel, V, Boivin, G, Rosa-Calatrava, M & Terrier, O 2019, 'The non-structural NS1 protein of influenza viruses modulates TP53 splicing through the host factor CPSF4', Journal of Virology, vol. 93, no. 7, e02168-18, pp. 1-19. https://doi.org/10.1128/JVI.02168-18

The non-structural NS1 protein of influenza viruses modulates TP53 splicing through the host factor CPSF4. / Dubois, Julia; Traversier, Aurélien; Julien, Thomas; Padey, Blandine; Lina, Bruno; Bourdon, Jean-Christophe; Marcel, Virginie; Boivin, Guy; Rosa-Calatrava, Manuel; Terrier, Olivier (Lead / Corresponding author).

In: Journal of Virology, Vol. 93, No. 7, e02168-18, 03.2019, p. 1-19.

Research output: Contribution to journalArticle

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AU - Dubois, Julia

AU - Traversier, Aurélien

AU - Julien, Thomas

AU - Padey, Blandine

AU - Lina, Bruno

AU - Bourdon, Jean-Christophe

AU - Marcel, Virginie

AU - Boivin, Guy

AU - Rosa-Calatrava, Manuel

AU - Terrier, Olivier

N1 - Copyright © 2019 American Society for Microbiology.

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N2 - Influenza A viruses (IAV) are known to modulate and "hijack" several cellular host mechanisms, including gene splicing and RNA maturation machineries. These modulations alter host cellular responses and enable an optimal expression of viral products throughout infection. The interplay between the host protein p53 and IAV, in particular through the viral nonstructural protein NS1, has been shown to be supportive for IAV replication. However, it remains unknown whether alternatively spliced isoforms of p53, known to modulate p53 transcriptional activity, are affected by IAV infection and contribute to IAV replication. Using a TP53 minigene, which mimics intron 9 alternative splicing, we have shown here that the NS1 protein of IAV changes the expression pattern of p53 isoforms. Our results demonstrate that CPSF4 (cellular protein cleavage and polyadenylation specificity factor 4) independently and the interaction between NS1 and CPSF4 modulate the alternative splicing of TP53 transcripts, which may result in the differential activation of p53-responsive genes. Finally, we report that CPSF4 and most likely beta and gamma spliced p53 isoforms affect both viral replication and IAV-associated type I interferon secretion. All together, our data show that cellular p53 and CPSF4 factors, both interacting with viral NS1, have a crucial role during IAV replication that allows IAV to interact with and alter the expression of alternatively spliced p53 isoforms in order to regulate the cellular innate response, especially via type I interferon secretion, and perform efficient viral replication.IMPORTANCE Influenza A viruses (IAV) constitute a major public health issue, causing illness and death in high-risk populations during seasonal epidemics or pandemics. IAV are known to modulate cellular pathways to promote their replication and avoid immune restriction via the targeting of several cellular proteins. One of these proteins, p53, is a master regulator involved in a large panel of biological processes, including cell cycle arrest, apoptosis, or senescence. This "cellular gatekeeper" is also involved in the control of viral infections, and viruses have developed a wide diversity of mechanisms to modulate/hijack p53 functions to achieve an optimal replication in their hosts. Our group and others have previously shown that p53 activity is finely modulated by different multilevel mechanisms during IAV infection. Here, we characterized IAV nonstructural protein NS1 and the cellular factor CPSF4 as major partners involved in the IAV-induced modulation of the TP53 alternative splicing that was associated with a strong modulation of p53 activity and notably the p53-mediated antiviral response.

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