Activation of cJUN N-Terminal Kinase by Herpes Simplex Virus Type 1 Enhances Viral Replication

Abstract

Signal transduction pathways convey signals generated at the cell surface into the cell nucleus in order to initiate a program of gene expression that is characteristic for particular stimuli. Here we present evidence that infection by herpes simplex virus type 1 activated the two terminal kinases, cJUN N-terminal kinase (JNK) and p38, of stress-activated signal transduction kinase cascades. By using a solid-phase kinase assay, a phospho-specific antibody, and extracts prepared from a variety of infected cell types, we determined that activation of both kinases began 3 to 4 h postinfection (p.i.) and remained elevated out to 14 h p.i. Through the use of UV-irradiated or antibody-neutralized wild-type virus and the temperature-sensitive mutant tsB7, the high level of JNK activation was shown to be dependent on viral gene expression. Activation of JNK following infection by vi13, an ICP4 mutant virus that does not express early or late genes, suggested that only virus entry and immediate-early gene expression were necessary for JNK activation. The activation of JNK and p38 correlated with increased chloramphenicol acetyltransferase (CAT) activity in reporter assays dependent upon the activity of cJUN and ATF2trans-activation domains. Increased CAT activity dependent on TRE and CRE promoter sites was also observed in response to herpes simplex virus infection. The activities of ERK and ERK-dependent transcription factors were unchanged or depressed following infection, showing that activation of JNK and p38 was a specific event. Finally, the activation of JNK was important for the efficiency of viral replication. The yield of virus in NIH 3T3 cells stably expressing JIP-1, an inhibitor of JNK translocation to the nucleus, was reduced 70% compared to that of control cells, in single-step growth experiments.

Activation of c-Jun N-terminal kinase (JNK) pathway by HSV-1 immediate early protein ICP0

“…1). Additionally, it was found that HSV-1 infection stimulated c-Jun N-terminal mitogen-activated protein kinase pathway [24,25]. These led us to speculate whether HSV-1 ICP0 stimulated gene transcription via promoting AP-1 activity.…”

Inhibitors of c-Jun N-terminal kinases—JuNK no more?

“…Increasingly, it has been shown that viral infection can lead to JNK activation. Examples include infection by Epstein-Barr Virus [33], Herpes Simplex Virus [34], Reovirus [35], Kaposi's Sarcoma Virus [36], or Varicella-Zoster virus [37,38]. Whilst the exact mechanisms leading to JNK activation remain to be evaluated in many of these cases, it is of interest that Kaposi's Sarcoma Virus encodes the viral kinase ORF36 that interacts with JNK as well as the upstream JNK pathway kinases MKK4 and MKK7.…”

BX-795 inhibits HSV-1 and HSV-2 replication by blocking the JNK/p38 pathways without interfering with PDK1 activity in host cells

“…Activated JNK/p38 MAP kinase can transmit upstream signals to downstream fac-tors, thus mediating cellular apoptosis, differentiation, growth or immune responses [4,5] . JNK and p38 MAP kinase are also reported to be stimulated by many viruses or virus-associated proteins, including rotavirus [6] , varicella-zoster virus (VZV) [7,8] , HIV-1 [9] , HSV-1 [10,11] , coxsackievirus B3 (CVB3) [12] , Epstein-Barr virus (EBV) [13] , severe acute respiratory syndrome (SARS) coronavirus [14] and hepatitis B/C virus (HBV/HCV) [15,16] . The activation of the JNK/p38 MAP kinase cascade induced by these viruses either facilitates the viral lytic cycle or serves as a defense mechanism of the host cells.…”

“…The activation of the JNK/p38 MAP kinase cascade induced by these viruses either facilitates the viral lytic cycle or serves as a defense mechanism of the host cells. Therefore, virusinduced activation of the JNK/p38 MAP kinase pathway is considered to be universally important for viral infection or cell survival [6,7,10,12,16] .…”