Herpes Simplex Virus Type 1 Infection Stimulates p38/c-Jun N-terminal Mitogen-activated Protein Kinase Pathways and Activates Transcription Factor AP-1

George Zachos,Barklie Clements,Joe Conner

doi:10.1074/jbc.274.8.5097

Abstract

Cells respond to environmental stress and proinflammatory cytokines by stimulating the Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and the p38 mitogen-activated protein kinase cascades. Infection of eukaryotic cells with herpes simplex virus type 1 (HSV-1) resulted in stimulation of both JNK/SAPK and p38 mitogen-activated protein kinase after 3 h of infection, and activation reached a maximum of 4-fold by 9 h post-infection. By using a series of mutant viruses, we showed that the virion transactivator protein VP16 stimulates p38/JNK, whereas no immediate-early, early, or late viral expressed gene is involved. We identified the stress-activated protein kinase kinase 1 as an upstream activator of p38/JNK, and we demonstrated that activation of AP-1 binding proceeded p38/JNK stimulation. During infection, the activated AP-1 consisted mainly of JunB and JunD with a simultaneous decrease in the cellular levels of Jun protein. We suggest that activation of the stress pathways by HSV-1 infection either represents a cascade triggered by the virus to facilitate the lytic cycle or a defense mechanism of the host cell against virus invasion.

Highlights

Cells respond to environmental stress and proinflammatory cytokines by stimulating the Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and the p38 mitogen-activated protein kinase cascades
Immunocomplexed p38 MAPK activity was determined in samples harvested at 2, 4, 6, 8, and 10 h postinfection (Fig. 2A, lanes 2– 6, respectively) and in untreated cells; Western blots were probed with an antibody specific for the phosphorylated form of activating transcription factor (ATF)-2 and demonstrated an increase in phosphorylation by 6 h, with a maximum activity detected at 10 h
A 5-fold activation was observed in control UV-irradiated cells. These results indicate that both p38 MAPK and JNK/SAPK are stimulated by wild-type herpes simplex virus type 1 (HSV-1) infection, and we considered the possibility that a viral protein was implicated in this phenomenon

Summary

Introduction

Cells respond to environmental stress and proinflammatory cytokines by stimulating the Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and the p38 mitogen-activated protein kinase cascades. Virus in1814 expresses an inactive form of virion protein VP16 which is defective in interacting with cellular factors Oct-1 and HCF and was a gift from Dr C.M. Preston, Institute of Virology, University of Glasgow, Glasgow, UK [36].

Results

Conclusion