Influenza A virus NS1 protein mimics oncogenic PI3K resulting in isoform specific cellular redistribution and activation

The nonstructural protein 1 (NS1) of influenza A virus performs a broad variety of proviral activities in the infected cell, primarily mediating evasion from the host innate immune response by being the main viral interferon antagonist. However, there are several interactions whose biological releva...

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Autores: Aslam, Sadaf, Sánchez-Aparicio, M. T., Siempelkamp, Braden D., Dornan, Gillian L., Tsolakos, Nikos, Burke, John E., Hale, Benjamin G., García Sastre, Adolfo, Ayllón Barasoain, Juan
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Universidad de Burgos (UBU)
Repositorio:Repositorio Institucional de la Universidad de Burgos (RIUBU)
OAI Identifier:oai:riubu.ubu.es:10259/10923
Acceso en línea:https://hdl.handle.net/10259/10923
Access Level:acceso abierto
Palabra clave:Influenza
Oncogenesis
PI3K
Proteínas
Proteins
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spelling Influenza A virus NS1 protein mimics oncogenic PI3K resulting in isoform specific cellular redistribution and activationAslam, SadafSánchez-Aparicio, M. T.Siempelkamp, Braden D.Dornan, Gillian L.Tsolakos, NikosBurke, John E.Hale, Benjamin G.García Sastre, AdolfoAyllón Barasoain, JuanInfluenzaOncogenesisPI3KProteínasProteinsThe nonstructural protein 1 (NS1) of influenza A virus performs a broad variety of proviral activities in the infected cell, primarily mediating evasion from the host innate immune response by being the main viral interferon antagonist. However, there are several interactions whose biological relevance remains obscure, such as the ability of NS1 to bind and activate class IA phosphoinositide 3-kinases (PI3Ks). PI3Ks are highly regulated lipid kinases that act as critical nodes in multiple cell signaling networks and are also important proto-oncogenes. This activation is mediated by NS1 binding specifically to the p85β subunit. To better understand the consequences of this interaction, we developed a bimolecular fluorescence complementation (BiFC) assay to selectively track the different PI3K heterodimers and, using this system, we found that NS1 induces an isoform-specific relocation and activation of the different PI3K heterodimers. We found that clinically relevant oncogenic mutations in both catalytic and regulatory subunits of PI3K could mimic the effect caused by NS1, and partially rescue the loss of viral fitness in a recombinant virus encoding a p85β-binding deficient NS1.We thank Richard Cadagan, Elena Moreno, and Sara El Zahed for technical assistance. Confocal laser scanning microscopy was performed at the Icahn School of Medicine Microscopy Shared Resource facility. This work was partly supported by CRIPT (Center for Research on Influenza Pathogenesis and Transmission), a NIAID funded Center of Excellence for Influenza Research and Response (CEIRR, contract #75N93021C00014) to A.G.- S. The work was also partially supported by the Swiss NSF (Grant 31003A_159993 to B.G.H.) and the Cancer Research Society (CRS- CRS- 1052949 to J.E.B.).National Academy of Sciences202520252025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/10259/10923reponame:Repositorio Institucional de la Universidad de Burgos (RIUBU)instname:Universidad de Burgos (UBU)InglésProceedings of the National Academy of Sciences. 2025, V.122, n. 32, e2423066122https://doi.org/10.1073/pnas.2423066122Attribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:riubu.ubu.es:10259/109232026-05-28T07:56:11Z
dc.title.none.fl_str_mv Influenza A virus NS1 protein mimics oncogenic PI3K resulting in isoform specific cellular redistribution and activation
title Influenza A virus NS1 protein mimics oncogenic PI3K resulting in isoform specific cellular redistribution and activation
spellingShingle Influenza A virus NS1 protein mimics oncogenic PI3K resulting in isoform specific cellular redistribution and activation
Aslam, Sadaf
Influenza
Oncogenesis
PI3K
Proteínas
Proteins
title_short Influenza A virus NS1 protein mimics oncogenic PI3K resulting in isoform specific cellular redistribution and activation
title_full Influenza A virus NS1 protein mimics oncogenic PI3K resulting in isoform specific cellular redistribution and activation
title_fullStr Influenza A virus NS1 protein mimics oncogenic PI3K resulting in isoform specific cellular redistribution and activation
title_full_unstemmed Influenza A virus NS1 protein mimics oncogenic PI3K resulting in isoform specific cellular redistribution and activation
title_sort Influenza A virus NS1 protein mimics oncogenic PI3K resulting in isoform specific cellular redistribution and activation
dc.creator.none.fl_str_mv Aslam, Sadaf
Sánchez-Aparicio, M. T.
Siempelkamp, Braden D.
Dornan, Gillian L.
Tsolakos, Nikos
Burke, John E.
Hale, Benjamin G.
García Sastre, Adolfo
Ayllón Barasoain, Juan
author Aslam, Sadaf
author_facet Aslam, Sadaf
Sánchez-Aparicio, M. T.
Siempelkamp, Braden D.
Dornan, Gillian L.
Tsolakos, Nikos
Burke, John E.
Hale, Benjamin G.
García Sastre, Adolfo
Ayllón Barasoain, Juan
author_role author
author2 Sánchez-Aparicio, M. T.
Siempelkamp, Braden D.
Dornan, Gillian L.
Tsolakos, Nikos
Burke, John E.
Hale, Benjamin G.
García Sastre, Adolfo
Ayllón Barasoain, Juan
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Influenza
Oncogenesis
PI3K
Proteínas
Proteins
topic Influenza
Oncogenesis
PI3K
Proteínas
Proteins
description The nonstructural protein 1 (NS1) of influenza A virus performs a broad variety of proviral activities in the infected cell, primarily mediating evasion from the host innate immune response by being the main viral interferon antagonist. However, there are several interactions whose biological relevance remains obscure, such as the ability of NS1 to bind and activate class IA phosphoinositide 3-kinases (PI3Ks). PI3Ks are highly regulated lipid kinases that act as critical nodes in multiple cell signaling networks and are also important proto-oncogenes. This activation is mediated by NS1 binding specifically to the p85β subunit. To better understand the consequences of this interaction, we developed a bimolecular fluorescence complementation (BiFC) assay to selectively track the different PI3K heterodimers and, using this system, we found that NS1 induces an isoform-specific relocation and activation of the different PI3K heterodimers. We found that clinically relevant oncogenic mutations in both catalytic and regulatory subunits of PI3K could mimic the effect caused by NS1, and partially rescue the loss of viral fitness in a recombinant virus encoding a p85β-binding deficient NS1.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/10259/10923
url https://hdl.handle.net/10259/10923
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Proceedings of the National Academy of Sciences. 2025, V.122, n. 32, e2423066122
https://doi.org/10.1073/pnas.2423066122
dc.rights.none.fl_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution-NonCommercial-NoDerivatives 4.0 Internacional
http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
dc.source.none.fl_str_mv reponame:Repositorio Institucional de la Universidad de Burgos (RIUBU)
instname:Universidad de Burgos (UBU)
instname_str Universidad de Burgos (UBU)
reponame_str Repositorio Institucional de la Universidad de Burgos (RIUBU)
collection Repositorio Institucional de la Universidad de Burgos (RIUBU)
repository.name.fl_str_mv
repository.mail.fl_str_mv
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