title: Loss of function of the influenza A virus NS1 protein promotes apoptosis but this is not due to a failure to activate phosphatidylinositol 3-kinase (PI3K).
abstract: A panel of influenza A viruses encoding mutant NS1 proteins was created in which a number of NS1 functions, including interactions with dsRNA, PI3K, CPSF30 and PKR, were inhibited. Surprisingly, given previous reports that NS1 activates PI3K to prevent apoptosis, the mutant viruses rUd-Y89F and rUd-P164/7A that fail to activate PI3K did not induce any more apoptosis than wild-type virus in MRC-5 and A549 cells, even though these cells are highly sensitive to inducers of apoptosis. Induction of cell death by the apoptogenic rUd-184-8(P) virus could not be prevented by serum-mediated activation of PI3K/Akt. Neither infection of MRC-5 or A549 cells with wild-type virus nor constitutive expression of NS1 prevented cell death caused by apoptosis inducers, suggesting that NS1 is not directly anti-apoptotic. Our data suggest that the loss of a functionally intact NS1 protein promotes apoptosis, but this is not due to an inability to activate PI3K.
authors.affiliation: Centre for Biomolecular Sciences, University of St. Andrews, St. Andrews, Fife, KY16 9ST, UK. dj10@st-andrews.ac.uk
authors.forename: David
authors.initials: D
authors.lastname: Jackson
authors.forename: Marian J
authors.initials: MJ
authors.lastname: Killip
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Galloway
authors.forename: Rupert J
authors.initials: RJ
authors.lastname: Russell
authors.forename: Richard E
authors.initials: RE
authors.lastname: Randall
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D039223:Cleavage And Polyadenylation Specificity Factor / Q000502:physiology; D004789:Enzyme Activation; D006801:Humans; D007372:Interferons / Q000096:biosynthesis; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000502:physiology*; D019892:eIF-2 Kinase / Q000502:physiology
chemical_list: D002867:Chromones; D039223:Cleavage And Polyadenylation Specificity Factor; C085820:INS1 protein, influenza virus; D009025:Morpholines; D017361:Viral Nonstructural Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007372:Interferons; D019869:Phosphatidylinositol 3-Kinases; D019892:eIF-2 Kinase