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J. Biol. Chem., Vol. 281, Issue 24, 16707-16715, June 16, 2006

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Membrane Accumulation of Influenza A Virus Hemagglutinin Triggers Nuclear Export of the Viral Genome via Protein Kinase C-mediated Activation of ERK Signaling^*

Henju Marjuki, Mohammad I. Alam, Christina Ehrhardt, Ralf Wagner^¶1, Oliver Planz^||, Hans-D. Klenk^¶, Stephan Ludwig, and Stephan Pleschka²

From the Institute for Medical Virology, Justus-Liebig-University, Frankfurter Strasse 107, D-35392 Giessen, the ^¶Institute for Virology, Philipps University, Robert-Koch Strasse 17, D-35037 Marburg, the ^||Friedrich-Loeffler-Institute, Federal Research Institute for Animal Health, Institute for Immunology, Paul-Ehrlich Strasse 28, D-72076 Tübingen, and the Institute for Molecular Virology, Westfälische-Wilhelms-University, von-Esmarch Strasse 56, D-48149 Münster, Germany

Replication and transcription of the influenza virus genome takes place exclusively within the nucleus of the infected cells. The viral RNA genome, polymerase subunits, and nucleoprotein form ribonucleoprotein (RNP) complexes. Late in the infectious cycle RNPs have to be exported from the nucleus to be enwrapped into budding progeny virions at the cell membrane. This process requires viral activation of the cellular Raf/MEK/ERK (mitogen-activated protein kinase (MAPK)) signaling cascade that is activated late in the infection cycle. Accordingly, block of the cascade results in retardation of RNP export and reduced titers of progeny virus. In the present study we have analyzed the importance of cell-membrane association of the viral hemagglutinin glycoprotein for viral MAPK activation. We show that hemagglutinin membrane accumulation and its tight association with lipid-raft domains trigger activation of the MAPK cascade via protein kinase C activation and induces RNP export. This may represent an auto-regulative mechanism that coordinates timing of RNP export to a point when all viral components are ready for virus budding.

Received for publication, September 16, 2005 , and in revised form, March 29, 2006.

^* This work was supported by grants of the Deutsche Forschungsgemeinschaft (Grants IIIGK-GRK370/3 and SFB 535 to S. P., SFB 593 to H.-D. K., and Lu 477/4-5 to S. L.). This work is part of the activities of the VIRGIL European Network of Excellence on Antiviral Drug Resistance supported by the Priority 1 Life Sciences, Genomics and Biotechnology for Health program in the 6th Framework Program of the EU (Grant LSHM-CT-2004-503359). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Paul-Ehrlich-Institute, Paul-Ehrlich Strasse 51-59, D-63225 Langen, Germany.

² To whom correspondence should be addressed: Tel.: 49-(0)641-99-47750; Fax: 49-(0)641-99-41209; E-mail: stephan.pleschka{at}mikro.bio.uni-giessen.de.

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