Varicella-zoster virus requires a functional PI3K/Akt/GSK-3α/β signaling cascade for efficient replication

Abstract

Successful replication of Varicella-zoster virus (VZV) relies upon strategies to counteract host defense mechanisms. This can be achieved by modulating host cell signaling pathways, which regulate apoptosis and cell survival. The Akt cascade is crucial for the regulation of cell survival since it controls factors such as Bad, FOXO1, mTor and GSK-3α/β. These factors are involved in the regulation of cell death, cell cycle and translation. Here, we report i) that the VZV infection of MeWo cells caused a 9 to 18-fold increased phosphorylation of Akt. This phosphorylation was independent from PI3K inasmuch as the PI3K phosphorylation pattern differed strongly from the one of Akt. Bad, FOXO1 and mTor showed also variations in their phosphorylation patterns: phosphorylation of Bad (ser-136) decreased during the infection while phosphorylation of ser-2448 of mTor and of ser-256 of FOXO1 increased. The phosphorylation of GSK-3α/β remained relatively stable during the infection. ii) Inhibition of PI3K, Akt or GSK-3α/β prior to infection resulted in a severe decline of viral replication. The inhibition of Akt resulted also in an increased apoptotic response. iii) Transfection studies using plasmids coding for functional or inactive VZV protein kinases, pORFs 47 and 66, demonstrated an increase in Akt phosphorylation. Infection of MeWo cells with VZVΔ47 and VZVΔ66 resulted in a decline of Akt and GSK-3α/β phosphorylation. These results suggest i) an essential role of PI3K/Akt/GSK-3α/β signaling for a successful replication of VZV and ii) a key function of VZV kinases pORFs 47 and 66 to activate this pathway.