title: Amplification of JNK signaling is necessary to complete the murine gammaherpesvirus 68 lytic replication cycle.
abstract: Several studies have previously defined host-derived signaling events capable of driving lytic gammaherpesvirus replication or enhancing immediate-early viral gene expression. Yet signaling pathways that regulate later stages of the productive gammaherpesvirus replication cycle are still poorly defined. In this study, we utilized a mass spectrometric approach to identify c-Jun as an abundant cellular phosphoprotein present in late stages of lytic murine gammaherpesvirus 68 (MHV68) infection. Kinetically, c-Jun phosphorylation was enhanced as infection progressed, and this correlated with enhanced phosphorylation of the c-Jun amino-terminal kinases JNK1 and JNK2 and activation of AP-1 transcription. These events were dependent on progression beyond viral immediate-early gene expression, but not dependent on viral DNA replication. Both pharmacologic and dominant-negative blockade of JNK1/2 activity inhibited viral replication, and this correlated with inhibition of viral DNA synthesis and reduced viral gene expression. These data suggest a model in which MHV68 by necessity amplifies and usurps JNK/c-Jun signaling as infection progresses in order to facilitate late stages of the MHV68 lytic infection cycle.
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Stahl
authors.forename: Clinton R
authors.initials: CR
authors.lastname: Paden
authors.forename: Shweta S
authors.initials: SS
authors.lastname: Chavan
authors.forename: Veronica
authors.initials: V
authors.lastname: MacLeod
authors.forename: Ricky D
authors.initials: RD
authors.lastname: Edmondson
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Speck
authors.forename: J Craig
authors.initials: JC
authors.lastname: Forrest
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018142:Gammaherpesvirinae / Q000502:physiology*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism; D014779:Virus Replication
chemical_list: D014764:Viral Proteins; D048670:MAP Kinase Kinase 4