title: Inability of NS1 protein from an H5N1 influenza virus to activate PI3K/Akt signaling pathway correlates to the enhanced virus replication upon PI3K inhibition.
abstract: BACKGROUND
  Phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, activated during influenza A virus infection, can promote viral replication via multiple mechanisms. Direct binding of NS1 protein to p85β subunit of PI3K is required for activation of PI3K/Akt signaling. Binding and subsequent activation of PI3K is believed to be a conserved character of influenza A virus NS1 protein. Sequence variation of NS1 proteins in different influenza A viruses led us to investigate possible deviation from the conservativeness.
  
  
  RESULTS
  In the present study, NS1 proteins from four different influenza A virus subtypes/strains were tested for their ability to bind p85β subunit of PI3K and to activate PI3K/Akt. All NS1 proteins efficiently bound to p85β and activated PI3K/Akt, with the exception of NS1 protein from an H5N1 virus (A/Chicken/Guangdong/1/05, abbreviated as GD05), which bound to p85β but failed to activate PI3K/Akt, implying that as-yet-unidentified domain(s) in NS1 may alternatively mediate the activation of PI3K. Moreover, PI3K inhibitor, LY294002, did not suppress but significantly increased the replication of GD05 virus.
  
  
  CONCLUSIONS
  Our study indicates that activation of PI3K/Akt by NS1 protein is not highly conserved among influenza A viruses and inhibition of the PI3K/Akt pathway as an anti-influenza strategy may not work for all influenza A viruses.
authors.affiliation: Department of Microbiology and Immunology, Key Immunopathology Laboratory of Guangdong Province, Shantou University Medical College, Shantou, 515041, China. ksli@stu.edu.cn.
authors.forename: Weizhong
authors.initials: W
authors.lastname: Li
authors.forename: Gefei
authors.initials: G
authors.lastname: Wang
authors.forename: Heng
authors.initials: H
authors.lastname: Zhang
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Shen
authors.forename: Jianping
authors.initials: J
authors.lastname: Dai
authors.forename: Liqi
authors.initials: L
authors.lastname: Wu
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Zhou
authors.forename: Zhiwu
authors.initials: Z
authors.lastname: Jiang
authors.forename: Kangsheng
authors.initials: K
authors.lastname: Li
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004285:Dogs; D006367:HeLa Cells; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000235:genetics* / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D008969:Molecular Sequence Data; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000662:veterinary; D016415:Sequence Alignment; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication
chemical_list: C085820:INS1 protein, influenza virus; D017361:Viral Nonstructural Proteins; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt