Reversal of Human Cytomegalovirus Major Immediate-Early Enhancer/Promoter Silencing in Quiescently Infected Cells via the Cyclic AMP Signaling Pathway
- 15 June 2007
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 81 (12), 6669-6681
- https://doi.org/10.1128/jvi.01524-06
Abstract
The human cytomegalovirus (HCMV) major immediate-early (MIE) enhancer contains five functional cyclic AMP (cAMP) response elements (CRE). Because the CRE in their native context do not contribute appreciably to MIE enhancer/promoter activity in lytically infected human fibroblasts and NTera2 (NT2)-derived neurons, we postulated that they might have a role in MIE enhancer/promoter reactivation in quiescently infected cells. Here, we show that stimulation of the cAMP signaling pathway by treatment with forskolin (FSK), an adenylyl cyclase activator, greatly alleviates MIE enhancer/promoter silencing in quiescently infected NT2 neuronal precursors. The effect is immediate, independent of de novo protein synthesis, associated with the phosphorylation of ATF-1 serine 63 and CREB serine 133, dependent on protein kinase A (PKA) and the enhancer's CRE, and linked to viral-lytic-cycle advancement. Coupling of FSK treatment with the inhibition of either histone deacetylases or protein synthesis synergistically activates MIE gene expression in a manner suggesting that MIE enhancer/promoter silencing is optimally relieved by an interplay of multiple regulatory mechanisms. In contrast, MIE enhancer/promoter silence is not overcome by stimulation of the gamma interferon (IFN-γ) signaling pathway, despite the enhancer having two IFN-γ-activated-site-like elements. We conclude that stimulation of the cAMP/PKA signaling pathway drives CRE-dependent MIE enhancer/promoter activation in quiescently infected cells, thus exposing a potential mode of regulation in HCMV reactivation.Keywords
This publication has 62 references indexed in Scilit:
- Human Cytomegalovirus Inhibits Neuronal Differentiation and Induces Apoptosis in Human Neural Precursor CellsJournal of Virology, 2006
- Lipopolysaccharide, Tumor Necrosis Factor Alpha, or Interleukin-1β Triggers Reactivation of Latent Cytomegalovirus in Immunocompetent MiceJournal of Virology, 2006
- An in vitro model for the regulation of human cytomegalovirus latency and reactivation in dendritic cells by chromatin remodellingJournal of General Virology, 2005
- Two Sp1/Sp3 Binding Sites in the Major Immediate-Early Proximal Enhancer of Human Cytomegalovirus Have a Significant Role in Viral ReplicationJournal of Virology, 2005
- Characterization of the Elements and Proteins Responsible for Interferon-Stimulated Gene Induction by Human CytomegalovirusJournal of Virology, 2005
- Cellular Repressor Inhibits Human Cytomegalovirus Transcription from the UL127 PromoterJournal of Virology, 2004
- The Human Cytomegalovirus Major Immediate-Early Enhancer Determines the Efficiency of Immediate-Early Gene Transcription and Viral Replication in Permissive Cells at Low Multiplicity of InfectionJournal of Virology, 2003
- Requirement of Multiple cis -Acting Elements in the Human Cytomegalovirus Major Immediate-Early Distal Enhancer for Viral Gene Expression and ReplicationJournal of Virology, 2002
- Depolarization Strongly Induces Human Cytomegalovirus Major Immediate-Early Promoter/Enhancer Activity in NeuronsPublished by Elsevier BV ,2001
- Transcriptional regulation by the phosphorylation-dependent factor CREBNature Reviews Molecular Cell Biology, 2001