Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade.
Influenza A viruses are important worldwide pathogens in humans and different animal species. The functions of most of the ten different viral proteins of this negative-strand RNA virus have been well elucidated. However, little is known about the virus-induced intracellular signalling events that support viral replication. The Raf/MEK/ERK cascade is the prototype of mitogen-activated protein (MAP) kinase cascades and has an important role in cell growth, differentiation and survival. Investigation of the function of this pathway has been facilitated by the identification of specific inhibitors such as U0126, which blocks the cascade at the level of MAPK/ERK kinase (MEK). Here we show that infection of cells with influenza A virus leads to biphasic activation of the Raf/MEK/ERK cascade. Inhibition of Raf signalling results in nuclear retention of viral ribonucleoprotein complexes (RNPs), impaired function of the nuclear-export protein (NEP/NS2) and concomitant inhibition of virus production. Thus, signalling through the mitogenic cascade seems to be essential for virus production and RNP export from the nucleus during the viral life cycle.
Institut für Virologie, Fachbereich Veterinärmedizin, Justus-Liebig Universität, D-35392 Giessen, Germany.
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S
Pleschka
T
T
Wolff
C
C
Ehrhardt
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G
Hobom
O
O
Planz
U R
UR
Rapp
S
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Ludwig
D021581:Active Transport, Cell Nucleus; D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017930:Genes, Reporter; D006801:Humans; D007150:Immunohistochemistry; D009980:Influenza A virus / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018613:Microscopy, Confocal; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism; D014162:Transfection; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication
D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D011993:Recombinant Fusion Proteins; D012261:Ribonucleoproteins; C113580:U 0126; D014764:Viral Proteins; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases