ORF61 protein of Varicella-zoster virus influences JNK/SAPK and p38/MAPK phosphorylation.
Recently, it was demonstrated that the Varicella-zoster virus (VZV) infection led to an activation of MAP kinases. The viral protein encoded by ORF61 is a major effector of JNK/SAPK and p38/MAPK phosphorylation. ORF61 shows homology to HSV-1 ICP0, a multifunctional protein that influences the activity of c-Jun in infected cells. Stable expression of ORF61 in a MeWo derived cell line gave rise to two specific effects: (i) a major decrease of VZV replication and (ii) a strongly elevated basal JNK/SAPK phosphorylation but a reduced p38/MAPK phosphorylation, which were both altered following infection. A dose-dependent inhibition of JNK/SAPK in MeWo/61 cells resulted in a step-by-step increase of VZV replication. These findings indicate (i) that ORF61 is responsible for the elevated JNK/SAPK phosphorylation and (ii) that the VZV replication and the JNK/SAPK phosphorylation are related inversely. Compared to MeWo cells, the basal phosphorylation of downstream targets c-Jun and ATF-2 was reduced following ORF61 expression but restored after infection. Subsequent cascades to induce inflammatory responses were activated insignificantly; cascades to activate apoptotic events also remained silent. These data point towards an important role of ORF61 in the fine-regulation of activation of the MAPK pathways and their downstream targets to optimize the availability of cellular factors involved in VZV gene expression.
Rahaus
Markus
M
Institute of Microbiology and Virology, University of Witten/Herdecke, Witten, Germany.
Desloges
Nathalie
N
Wolff
Manfred H
MH
D051698:Activating Transcription Factor 2; D017209:Apoptosis; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D014645:Herpesvirus 3, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020935:MAP Kinase Signaling System; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D010948:Viral Plaque Assay; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D014764:Viral Proteins; C073411:protein 61, Varicella-zoster virus; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases