title: Focal adhesion kinase (FAK) regulates polymerase activity of multiple influenza A virus subtypes.
abstract: Influenza A viruses (IAVs) cause numerous pandemics and yearly epidemics resulting in ~500,000 annual deaths globally. IAV modulates cellular signaling pathways at every step of the infection cycle. Focal adhesion kinase (FAK) has been shown to play a critical role in endosomal trafficking of influenza A viruses, yet it is unclear how FAK kinase activity regulates IAV replication. Using mini-genomes derived from H1N1, H5N1 and H7N9 viruses, we dissected RNA replication by IAVs independent of viral entry or release. Our results show FAK activity promotes efficient IAV polymerase activity and inhibiting FAK activity with a chemical inhibitor or a kinase-dead mutant significantly reduces IAV polymerase activity. Using co-immunoprecipitations and proximity ligation assays, we observed interactions between FAK and the viral nucleoprotein, supporting a direct role of FAK in IAV replication. Altogether, the data indicates that FAK kinase activity is important in promoting IAV replication by regulating its polymerase activity.
authors.affiliation: Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: helbahes@uthsc.edu.
authors.forename: Husni
authors.initials: H
authors.lastname: Elbahesh
authors.affiliation: Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Silke
authors.initials: S
authors.lastname: Bergmann
authors.affiliation: Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Russell
mesh_terms: D000818:Animals; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D053124:Influenza A Virus, H5N1 Subtype / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D064766:Influenza A Virus, H7N9 Subtype / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D007251:Influenza, Human / Q000201:enzymology* / Q000235:genetics / Q000821:virology; D009698:Nucleoproteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D009698:Nucleoproteins; D014764:Viral Proteins; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D004259:DNA-Directed DNA Polymerase
keywords: Focal adhesion kinase; Influenza A virus; Kinase-dead; Minigenome; Nucleoprotein; Polymerase activity; Proximity ligation assay; Replication