Neuronal Stress Pathway Mediating a Histone Methyl/Phospho Switch Is Required for Herpes Simplex Virus Reactivation

• Published in: Cell host & microbe 2015-12, Vol.18 (6), p.649-658
• Main Authors: Cliffe, Anna R., Arbuckle, Jesse H., Vogel, Jodi L., Geden, Matthew J., Rothbart, Scott B., Cusack, Corey L., Strahl, Brian D., Kristie, Thomas M., Deshmukh, Mohanish
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Gene Expression Regulation; Histones - metabolism; Mice; Neurons - virology; Phosphorylation; Promoter Regions, Genetic; Protein Processing, Post-Translational; Signal Transduction; Simplexvirus - genetics; Simplexvirus - physiology; Stress, Physiological; Virus Activation
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2015.11.007

Herpes simplex virus (HSV) reactivation from latent neuronal infection requires stimulation of lytic gene expression from promoters associated with repressive heterochromatin. Various neuronal stresses trigger reactivation, but how these stimuli activate silenced promoters remains unknown. We show that a neuronal pathway involving activation of c-Jun N-terminal kinase (JNK), common to many stress responses, is essential for initial HSV gene expression during reactivation. This JNK activation in neurons is mediated by dual leucine zipper kinase (DLK) and JNK-interacting protein 3 (JIP3), which direct JNK toward stress responses instead of other cellular functions. Surprisingly, JNK-mediated viral gene induction occurs independently of histone demethylases that remove repressive lysine modifications. Rather, JNK signaling results in a histone methyl/phospho switch on HSV lytic promoters, a mechanism permitting gene expression in the presence of repressive lysine methylation. JNK is present on viral promoters during reactivation, thereby linking a neuronal-specific stress pathway and HSV reactivation from latency. [Display omitted] •Neuronal-specific JNK stress pathway is critical for HSV reactivation from latency•JNK is required for the first phase of HSV lytic gene expression in reactivation•First phase of lytic gene expression is independent of histone demethylase activity•JNK signaling results in a histone methyl/phospho switch on HSV lytic gene promoters Stress stimulates HSV reactivation from latent infection through unknown mechanisms. Cliffe et al. show that a neuronal stress pathway involving cJun N-terminal kinase (JNK) activation is crucial for HSV reactivation. JNK signaling induces histone phosphorylation on repressed viral promoters, therefore linking cell stress with initial stimulation of viral gene expression.