ORF61 protein of Varicella-zoster virus influences JNK/SAPK and p38/MAPK phosphorylation

Abstract

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.