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Phosphoproteomic analyses reveal signaling pathways that facilitate lytic gammaherpesvirus replication.

Abstract
Lytic gammaherpesvirus (GHV) replication facilitates the establishment of lifelong latent infection, which places the infected host at risk for numerous cancers. As obligate intracellular parasites, GHVs must control and usurp cellular signaling pathways in order to successfully replicate, disseminate to stable latency reservoirs in the host, and prevent immune-mediated clearance. To facilitate a systems-level understanding of phosphorylation-dependent signaling events directed by GHVs during lytic replication, we utilized label-free quantitative mass spectrometry to interrogate the lytic replication cycle of murine gammaherpesvirus-68 (MHV68). Compared to controls, MHV68 infection regulated by 2-fold or greater ca. 86% of identified phosphopeptides - a regulatory scale not previously observed in phosphoproteomic evaluations of discrete signal-inducing stimuli. Network analyses demonstrated that the infection-associated induction or repression of specific cellular proteins globally altered the flow of information through the host phosphoprotein network, yielding major changes to functional protein clusters and ontologically associated proteins. A series of orthogonal bioinformatics analyses revealed that MAPK and CDK-related signaling events were overrepresented in the infection-associated phosphoproteome and identified 155 host proteins, such as the transcription factor c-Jun, as putative downstream targets. Importantly, functional tests of bioinformatics-based predictions confirmed ERK1/2 and CDK1/2 as kinases that facilitate MHV68 replication and also demonstrated the importance of c-Jun. Finally, a transposon-mutant virus screen identified the MHV68 cyclin D ortholog as a viral protein that contributes to the prominent MAPK/CDK signature of the infection-associated phosphoproteome. Together, these analyses enhance an understanding of how GHVs reorganize and usurp intracellular signaling networks to facilitate infection and replication.
AuthorsJames A Stahl, Shweta S Chavan, Jeffrey M Sifford, Veronica MacLeod, Daniel E Voth, Ricky D Edmondson, J Craig Forrest
JournalPLoS pathogens (PLoS Pathog) Vol. 9 Issue 9 Pg. e1003583 (Sep 2013) ISSN: 1553-7374 [Electronic] United States
PMID24068923 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Validation Study)
Chemical References
  • Cyclin D
  • Phosphoproteins
  • Proteome
  • Proto-Oncogene Proteins c-jun
  • Viral Proteins
Topics
  • 3T3 Cells
  • Animals
  • Chromatography, High Pressure Liquid
  • Computational Biology
  • Cyclin D (chemistry, genetics, metabolism)
  • Gammaherpesvirinae (genetics, physiology)
  • Herpesviridae Infections (metabolism, virology)
  • Host-Pathogen Interactions
  • MAP Kinase Signaling System
  • Mice
  • Models, Biological
  • Mutation
  • Phosphoproteins (chemistry, genetics, metabolism)
  • Proteome (chemistry, metabolism)
  • Proteomics (methods)
  • Proto-Oncogene Proteins c-jun (chemistry, metabolism)
  • Signal Transduction
  • Tandem Mass Spectrometry
  • Viral Proteins (chemistry, genetics, metabolism)
  • Virus Replication

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