Amplification of JNK signaling is necessary to complete the murine gammaherpesvirus 68 lytic replication cycle

J Virol. 2012 Dec;86(24):13253-62. doi: 10.1128/JVI.01432-12. Epub 2012 Sep 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Gammaherpesvirinae / physiology*
  • Humans
  • MAP Kinase Kinase 4 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Signal Transduction*
  • Tandem Mass Spectrometry
  • Viral Proteins / chemistry
  • Viral Proteins / metabolism
  • Virus Replication*


  • Viral Proteins
  • MAP Kinase Kinase 4