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Journal of Virology, April 2007, p. 3058-3067, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02082-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Christina Ehrhardt,1 Thorsten Wolff,2 Stephan Pleschka,3 Oliver Planz,4 Wiebke Beermann,2 Johannes G. Bode,5 Mirco Schmolke,1 and Stephan Ludwig1*

Institute of Molecular Virology, ZMBE, Westfaelische-Wilhelms-University, Von Esmarch-Str. 56, D-48149 Muenster, Germany,1 Robert-Koch-Institute, P15, Nordufer 20, D-13353 Berlin, Germany,2 Institute of Medical Virology, Justus-Liebig-University, Frankfurter Strasse 107, D-35392 Giessen, Germany,3 Friedrich-Loeffler-Institute, Paul-Ehrlich-Strasse 28, D-72076 Tübingen, Germany,4 Klinik fuer Gastroenterologie, Hepatologie und Infektiologie, Heinrich-Heine-University, D-40225 Duesseldorf, Germany5

Received 22 September 2006/ Accepted 22 December 2006

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 3ß and limitation of the virus-induced cell death program. Thus, NS1 not only blocks but also activates signaling pathways to ensure efficient virus replication.

* Corresponding author. Mailing address: Institute of Molecular Virology, Westfaelische-Wilhelms-University, Von-Esmarch-Str. 56, D-48149 Muenster, Germany. Phone: 49 251 83 57791. Fax: 49 251 83 57793. E-mail: ludwigs{at}uni-muenster.de.

{triangledown} Published ahead of print on 17 January 2007.

Journal of Virology, April 2007, p. 3058-3067, Vol. 81, No. 7
0022-538X/07/$08.00+0     doi:10.1128/JVI.02082-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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