Influenza A Virus NS1 Protein Activates the PI3K/Akt Pathway To Mediate Antiapoptotic Signaling Responses

• DOI: 10.1128/jvi.02082-06
• Publication Date: 2007-01-18T01:34:42Z
• Authors: Christina Ehrhardt; Thorsten Wolff; Stephan Pleschka; Oliver Planz; Wiebke Beermann; Johannes G. Bode; Mirco Schmolke; Stephan Ludwig
• Keywords: Gene Expression Regulation, Viral; 0303 health sciences; Influenza A Virus, H5N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H7N7 Subtype; Apoptosis; Cell Line; 3. Good health; Enzyme Activation; Isoenzymes; Phosphatidylinositol 3-Kinases; Protein Subunits; 03 medical and health sciences; Dogs; Influenza A Virus, H1N1 Subtype; Influenza A virus; Chlorocebus aethiops; Mutation; Animals; Humans; Phosphorylation; Proto-Oncogene Proteins c-akt; Protein Binding

ABSTRACT Recently we have shown that influenza A virus infection leads to activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and that this cellular reaction is dependent on the expression of the viral nonstructural protein 1 (NS1). These data also suggested that PI3K activation confers a virus-supporting activity at intermediate stages of the infection cycle. So far it is not known which process is regulated by the kinase that supports virus replication. It is well established that upon infection with influenza A virus, the expression of the viral NS1 keeps the induction of beta interferon and the apoptotic response within a tolerable limit. On a molecular basis, this activity of NS1 has been suggested to preclude the activation of cellular double-stranded RNA receptors as well as impaired modulation of mRNA processing. Here we present a novel mode of action of the NS1 protein to suppress apoptosis induction. NS1 binds to and activates PI3K, which results in the activation of the PI3K effector Akt. This leads to a subsequent inhibition of caspase 9 and glycogen synthase-kinase 3β and limitation of the virus-induced cell death program. Thus, NS1 not only blocks but also activates signaling pathways to ensure efficient virus replication.