This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Google Scholar
Right arrow Articles by Yuan, J.
Right arrow Articles by Meier, J. L.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Yuan, J.
Right arrow Articles by Meier, J. L.

 Previous Article  |  Next Article 

Journal of Virology, July 2009, p. 6391-6403, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00061-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Breaking Human Cytomegalovirus Major Immediate-Early Gene Silence by Vasoactive Intestinal Peptide Stimulation of the Protein Kinase A-CREB-TORC2 Signaling Cascade in Human Pluripotent Embryonal NTera2 Cells{triangledown}

Jinxiang Yuan,1,{dagger} Xiaoqiu Liu,1,{dagger} Allen W. Wu,1,2 Patrick W. McGonagill,1,2 Michael J. Keller,1 Courtney S. Galle,1 and Jeffery L. Meier1,2*

Department of Internal Medicine, University of Iowa Carver College of Medicine,1 Department of Internal Medicine, Veterans Affairs Medical Center, Iowa City, Iowa 522422

Received 11 January 2009/ Accepted 7 April 2009

The triggering mechanisms underlying reactivation of human cytomegalovirus (HCMV) in latently infected persons are unclear. During latency, HCMV major immediate-early (MIE) gene expression breaks silence to initiate viral reactivation. Using quiescently HCMV-infected human pluripotent embryonal NTera2 cells (NT2) to model HCMV reactivation, we show that vasoactive intestinal peptide (VIP), an immunomodulatory neuropeptide, immediately and dose-dependently (1 to 500 nM) activates HCMV MIE gene expression. This response requires the MIE enhancer cyclic AMP response elements (CRE). VIP quickly elevates CREB Ser133 and ATF-1 Ser63 phosphorylation levels, although the CREB Ser133 phosphorylation level is substantial at baseline. VIP does not change the level of HCMV genomes in nuclei, Oct4 (pluripotent cell marker), or hDaxx (cellular repressor of HCMV gene expression). VIP-activated MIE gene expression is mediated by cellular protein kinase A (PKA), CREB, and TORC2. VIP induces PKA-dependent TORC2 Ser171 dephosphorylation and nuclear entry, which likely enables MIE gene activation, as TORC2 S171A (devoid of Ser171 phosphorylation) exhibits enhanced nuclear entry and desilences the MIE genes in the absence of VIP stimulation. In conclusion, VIP stimulation of the PKA-CREB-TORC2 signaling cascade activates HCMV CRE-dependent MIE gene expression in quiescently infected NT2 cells. We speculate that neurohormonal stimulation via this signaling cascade is a possible means for reversing HCMV silence in vivo.

* Corresponding author. Mailing address: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA 52242. Phone: (319) 335-7906. Fax: (319) 335-9006. E-mail: jeffery-meier{at}uiowa.edu

{triangledown} Published ahead of print on 15 April 2009.

{dagger} J.Y. and X.L. contributed equally to this study.

Journal of Virology, July 2009, p. 6391-6403, Vol. 83, No. 13
0022-538X/09/$08.00+0     doi:10.1128/JVI.00061-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»