Influenza virus-induced AP-1-dependent gene expression requires activation of the JNK signaling pathway.
Influenza A virus infection of cells results in the induction of a variety of antiviral cytokines, including those that are regulated by transcription factors of the activating protein-1 (AP-1) family. Here we show that influenza virus infection induces AP-1-dependent gene expression in productively infected cells but not in cells that do not support viral replication. Among the AP-1 factors identified to bind to their cognate DNA element during viral infections of Madin-Darby canine kidney and U937 cells are those that are regulated via phosphorylation by JNKs. Accordingly, we observed that induction of AP-1-dependent gene expression correlates with a strong activation of JNK in permissive cells, which appears to be caused by viral RNA accumulation during replication. Blockade of JNK signaling at several levels of the cascade by transient expression of dominant negative kinase mutants and inhibitory proteins resulted in inhibition of virus-induced JNK activation, reduced AP-1 activity, and impaired transactivation of the IFN-beta promoter. Virus yields from transfected and infected cells in which JNK signaling was inhibited were higher compared with the levels from control cells. Therefore, we conclude that virus-induced activation of JNK and AP-1 is part of the innate antiviral response of the cell.
Ludwig
S
S
Institut für Medizinische Strahlenkunde und Zellforschung, Julius-Maximilians Universität, D-97078 Würzburg, Germany.
Ehrhardt
C
C
Neumeier
E R
ER
Kracht
M
M
Rapp
U R
UR
Pleschka
S
S
D000818:Animals; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D006801:Humans; D007251:Influenza, Human / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009975:Orthomyxoviridae / Q000502:physiology*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014779:Virus Replication
D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases