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oai:riubu.ubu.es:10259/109232025-10-04T00:05:28Zcom_10259_4862com_10259_5086com_10259_2604col_10259_4863

Influenza A virus NS1 protein mimics oncogenic PI3K resulting in isoform specific cellular redistribution and activation 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 Influenza Oncogenesis PI3K Proteínas Proteins 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. 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.). 2025-10-03T12:13:48Z 2025-10-03T12:13:48Z 2025-08 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 1091-6490 https://hdl.handle.net/10259/10923 10.1073/pnas.2423066122 eng Proceedings of the National Academy of Sciences. 2025, V.122, n. 32, e2423066122 https://doi.org/10.1073/pnas.2423066122 Attribution-NonCommercial-NoDerivatives 4.0 Internacional http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess application/pdf National Academy of Sciences https://riubu.ubu.es/bitstream/10259/10923/4/Aslam-pnas%20_2025.pdf.jpg Hispana TEXT http://creativecommons.org/licenses/by-nc-nd/4.0/ RIUBU. Repositorio Institucional de la Universidad de Burgos https://hdl.handle.net/10259/10923