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J Virol. 2019 Jan 16. pii: JVI.02168-18. doi: 10.1128/JVI.02168-18. [Epub ahead of print]
The non-structural NS1 protein of influenza viruses modulates TP53 splicing through the host factor CPSF4.
Dubois J1,2, Traversier A1, Julien T1, Padey B1, Lina B1,3, Bourdon JC4, Marcel V5, Boivin G2, Rosa-Calatrava M1,1, Terrier O6.
Author information
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 in 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 demonstrated 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 reported that CPSF4 and most likely beta and gamma spliced p53 isoforms affect both viral replication and IAV-associated type I interferon secretion. Altogether, our data showed that cellular p53 and CPSF4 factors, both interacting with viral NS1, have a crucial role during IAV replication that allows IAV to interact 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.ImportanceInfluenza 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 was finely modulated by different multi-level mechanisms during IAV infection. Here, we characterized IAV non-structural 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.
Copyright ? 2019 American Society for Microbiology.
PMID: 30651364 DOI: 10.1128/JVI.02168-18
The non-structural NS1 protein of influenza viruses modulates TP53 splicing through the host factor CPSF4.
Dubois J1,2, Traversier A1, Julien T1, Padey B1, Lina B1,3, Bourdon JC4, Marcel V5, Boivin G2, Rosa-Calatrava M1,1, Terrier O6.
Author information
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 in 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 demonstrated 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 reported that CPSF4 and most likely beta and gamma spliced p53 isoforms affect both viral replication and IAV-associated type I interferon secretion. Altogether, our data showed that cellular p53 and CPSF4 factors, both interacting with viral NS1, have a crucial role during IAV replication that allows IAV to interact 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.ImportanceInfluenza 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 was finely modulated by different multi-level mechanisms during IAV infection. Here, we characterized IAV non-structural 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.
Copyright ? 2019 American Society for Microbiology.
PMID: 30651364 DOI: 10.1128/JVI.02168-18