JNK Regulates Viral Gene Transcription During HSV-1 Infection

Herpes simplex virus 1 and 2(HSV-1 and HSV-2)are two members of the human herpesviridae family that causes a variety of diseases.According to two recent reports from the World Health Organization(WHO),two thirds of the world population under the age of 50 had prevalent HSV-1 infection,while over 550 million individuals of 15-49 years old had genital herpes.Both of the viruses can cause lytic infection in epithelial cells and reside in host sensory neurons to establish a life-long latency.The molecular events that trigger the switch from latent to productive lytic infection are not well understood.It is known that stress conditions can reactivate HSV-1 from latency.Based on the fact that most of the factors that can cause HSV reactivation can also activate JNK signaling pathway,we hypothesized that JNK signaling regulates HSV-1 reactivation and infection.The C-Jun N-terminal kinases(JNK),also known as stress-activated protein kinases(SAPK),are involved in a signal transduction pathway parallel to that of mitogen-activated protein kinases(MAPK).JNK regulates the process of cell growth,differentiation and stress response.Moreover,it was reported that HSV lytic infection stimulates the activation of JNK pathway,which is also essential for initial HSV gene expression during reactivation.In this study,we first explored the role of JNK in HSV-1 lytic infection and verified that HSV-1 ly₄tic infection really requires activation of JNK pathway.Next,HMBA(Hexamethylene bisacetamide)was used to explore the molecular mechanism of JNK in HSV lytic infection.we show that HMBA promotes transcription complex formation for viral gene expression though JNK modulated BRD4 transition.Specifically,HMBA treatment caused transient release of P-TEFb(Positive transcription elongation factor b)from transcriptionally inactive complex to being associated with Brd4,and subsequently redistribution to viral gene promoters.Furthermore,we showed that the effect was dependent on JNK since suppression of JNK expression,particularly JNK2 expression,blocked BRD4dissociation from chromatin targeting and its binding to P-TEFb.Moreover,inhibition of JNK activity or suppression of JNK2,and JNK1 to a less degree,overwhelmingly blocked HSV-1 infection and HMBA effect on HSV-1 infection.Finally,since commonly used antineoplastic drugs are JNK activators,we explored and verified that anti-tumor compounds may promote HSV infection by activating the JNK pathway.Together,these results demonstrated that JNK regulates HSV infection and reactivation through gene transcription.The study also implies that JNK activation and signal transduction may contribute to recurrent herpetic infections in patients undergoing antineoplastic treatment.Understanding its role of JNK in HSV-1 infection and reactivation has potential significance clinically.