Membrane accumulation of influenza A virus hemagglutinin triggers nuclear export of the viral genome via protein kinase Calpha-mediated activation of ERK signaling.

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 Calpha 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.