Influenza A virus NS1 protein activates the PI3K/Akt pathway to mediate antiapoptotic signaling responses.
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 3beta and limitation of the virus-induced cell death program. Thus, NS1 not only blocks but also activates signaling pathways to ensure efficient virus replication.
Ehrhardt
Christina
C
Institute of Molecular Virology, Westfaelische-Wilhelms-University, Von-Esmarch-Strasse 56, D-48149 Muenster, Germany.
Wolff
Thorsten
T
Pleschka
Stephan
S
Planz
Oliver
O
Beermann
Wiebke
W
Bode
Johannes G
JG
Schmolke
Mirco
M
Ludwig
Stephan
S
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002522:Chlorocebus aethiops; D004285:Dogs; D004789:Enzyme Activation; D015967:Gene Expression Regulation, Viral; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D053122:Influenza A Virus, H3N2 Subtype; D053124:Influenza A Virus, H5N1 Subtype; D053126:Influenza A Virus, H7N7 Subtype; D009980:Influenza A virus / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*
D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D021122:Protein Subunits; D051057:Proto-Oncogene Proteins c-akt; D017361:Viral Nonstructural Proteins; C085820:INS1 protein, influenza virus