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 fur Medizinische Strahlenkunde und Zellforschung, Julius-Maximilians Universitat, D-97078 Wurzburg, Germany. s.ludwig@mail.uni-wuerzburg.de
Ehrhardt
C
C
Neumeier
E R
ER
Kracht
M
M
Rapp
U R
UR
Pleschka
S
S
D051698:Activating Transcription Factor 2; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004789:Enzyme Activation; D015967:Gene Expression Regulation, Viral; D006367:HeLa Cells; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D016899:Interferon-beta / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012367:RNA, Viral / Q000378:metabolism; D013045:Species Specificity; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D020298:U937 Cells; D014779:Virus Replication
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D012367:RNA, Viral; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D016899:Interferon-beta; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; C482559:MAP2K4 protein, human; C482569:MAP2K7 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D004259:DNA-Directed DNA Polymerase