Replication of varicella-zoster virus is influenced by the levels of JNK/SAPK and p38/MAPK activation

Abstract

Stimulation of the Jun NH 2 -terminal kinase/stress-activated protein kinase (JNK/SAPK) and the p38 mitogen-activated protein kinase (p38/MAPK) is part of the stress-related signal transduction pathways conveying signals from the cell surface into the nucleus in order to initiate programmes of gene expression. Here, it was shown that infection by varicella-zoster virus (VZV) caused a 34-fold increase in activation of JNK/SAPK in the early phase of infection and a 2-fold increase in activation of p38/MAPK in the later phase. The phosphorylation of downstream targets c-Jun and ATF-2 was also increased; subsequent cascades to induce pro-inflammatory responses were significantly activated whereas cascades to activate apoptotic events were not. In the late phase of infection, both JNK/SAPK and p38/MAPK activities were reduced to basal levels. The use of specific inhibitors demonstrated that inhibition of JNK/SAPK resulted in a 2-fold increase in VZV replication whereas a strong decrease in virus replication was observed after inhibition of p38/MAPK. In contrast, constitutive activation of JNK/SAPK resulted in a decline in VZV replication. Blocking gene expression by treating cells with actinomycin D or cycloheximide prior to infection resulted in activation of neither JNK/SAPK nor p38/MAPK. It was assumed that the presence of tegument proteins was not sufficient to activate stress pathways, but that expression of viral genes was necessary. This suggests that activation of stress pathways by VZV infection represents a finely regulated system that activates cellular transcription factors for transregulation of VZV-encoded genes, but prevents activation of cellular defence mechanisms.

Cell Entry of Avian Reovirus Follows a Caveolin-1-mediated and Dynamin-2-dependent Endocytic Pathway That Requires Activation of p38 Mitogen-activated Protein Kinase (MAPK) and Src Signaling Pathways as Well as Microtubules and Small GTPase Rab5 Protein

“…An increasing amount of information has demonstrated that many viruses activate the p38 MAPK pathway to augment their efficient replication (51)(52)(53)(54)(55). To this end, although in our earlier study we have demonstrated that p38 MAPK activation is beneficial for ARV replication (31), its precise role in regulating ARV entry and replication remains elusive so far.…”

Virus-Induced Inhibition of CD1d1-Mediated Antigen Presentation: Reciprocal Regulation by p38 and ERK

“…ERK1/2 is known to be activated through the Ras/Raf/MEK pathway in response to various growth factors and to play a central role in cell proliferation (43). The replication of varicella zoster virus is positively regulated by activated p38, and the activation of this stress pathway activates cellular transcription factors, but prevents the activation of cellular defense mechanisms (44). MAPKs (including p38) have been shown to play important roles in the immune response from Th1/Th2 differentiation (14,19,45) to the host's defense against various pathogens, including viruses (19,46,47).…”

Uses for JNK: the Many and Varied Substrates of the c-Jun N-Terminal Kinases

“…There is also an increasing body of literature showing that JNK activation follows bacterial, fungal, prion, parasitic, or viral infections. Under these circumstances, JNK activation may influence important cellular consequences, such as alterations in gene expression (1,53,59,162,167,176,199,294,325,326,346), cell death (58,89,137,139,169,193,243,293), viral replication, persistent infection or progeny release (215,224,251,260), or altered cellular proliferation (178). The exact mechanism of JNK activation under each of these circumstances remains to be elucidated fully, although there may be involvement of Toll-like receptors, direct pathway modulation through interaction with upstream protein regulators, or the activation following an ER stress response (79,87,110,124,143,191,253,261,279,294,312).…”