title: Varicella-zoster virus influences the activities of components and targets of the ERK signalling pathway.
abstract: Varicella-zoster virus (VZV) is ultimately dependent upon its host cell for replication. To ensure its reproduction, VZV reorganizes various cellular functions by taking advantage of pre-existing signalling pathways. Recently, it was demonstrated that the activation of stress-related mitogen-activated protein kinase pathways following infection led to increased phosphorylation of cellular transcription factors involved in VZV gene expression. Here, it was shown that members of the extracellular signal-regulated kinase (ERK) pathway are also influenced following VZV infection: c-Raf remained inactive in infected MeWo cells, whereas MEK1/2 and ERK1/2 were phosphorylated transiently, reaching their highest level of phosphorylation at between 10 and 12 h post-infection. Inhibition of this pathway resulted in a severe reduction in viral progeny and in an increased apoptotic response, indicating that the functionality of this cascade is essential for successful high-rate replication. In addition, the activities of Bad, a cytoplasmic target of ERK via ribosomal S6 kinase, and the nuclear-localized target c-Myc were analysed. Bad is a member of the Bcl-2 family and has a key function in regulating apoptosis. Pro-apoptotic functions of Bad are repressed by phosphorylation. A 10-fold increase in Bad phosphorylation at Ser-112 was detected following infection, which was suppressed after inhibition of ERK. The transcription factor c-Myc is involved in the regulation of cell growth and apoptosis. By performing immunoblots and quantitative RT-PCR, suppression of c-Myc expression was demonstrated at both the transcriptional and translational levels in VZV-infected cells. These results suggest that VZV optimizes the conditions for its replication in different ways: upregulation of proviral-acting systems and suppression of potentially antiviral-acting systems.
authors.affiliation: Institute of Microbiology and Virology, University of Witten/Herdecke, Stockumer Strasse 10, D-58448 Witten, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Rahaus
authors.affiliation: Institute of Microbiology and Virology, University of Witten/Herdecke, Stockumer Strasse 10, D-58448 Witten, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Desloges
authors.affiliation: Institute of Microbiology and Virology, University of Witten/Herdecke, Stockumer Strasse 10, D-58448 Witten, Germany.
authors.forename: Manfred H
authors.initials: MH
authors.lastname: Wolff
mesh_terms: D004789:Enzyme Activation; D005786:Gene Expression Regulation; D014645:Herpesvirus 3, Human / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014779:Virus Replication
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C482128:MAP2K2 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human