title: Neuronal Stress Pathway Mediating a Histone Methyl/Phospho Switch Is Required for Herpes Simplex Virus Reactivation.
abstract: 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.
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: cliffe@email.unc.edu.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Cliffe
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jesse H
authors.initials: JH
authors.lastname: Arbuckle
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jodi L
authors.initials: JL
authors.lastname: Vogel
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Geden
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Scott B
authors.initials: SB
authors.lastname: Rothbart
authors.affiliation: Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neurobiology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Corey L
authors.initials: CL
authors.lastname: Cusack
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Strahl
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Kristie
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: mohanish@med.unc.edu.
authors.forename: Mohanish
authors.initials: M
authors.lastname: Deshmukh
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000821:virology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D018139:Simplexvirus / Q000235:genetics / Q000502:physiology*; D013312:Stress, Physiological; D014775:Virus Activation
chemical_list: D006657:Histones