NDLI: PI(3)K-Dependent Upregulation of Mcl-1 by Human Cytomegalovirus is Mediated by Epidermal Growth Factor Receptor and Inhibits Apoptosis in Short-Lived Monocytes

Content Provider	PubMed Central
Author	Chan, Gary Nogalski, Maciej T. Bentz, Gretchen L. Smith, M. Shane Alexander, Parmater Yurochko, Andrew D.
Abstract	Monocytes are a primary target for HCMV infection and are a key cell type responsible for hematogenous dissemination of the virus. Biologically these cells have a short life span of 1–3 days in the circulation, yet infected cells remain viable for weeks despite the lack of viral anti-apoptotic gene expression during this time period. To understand the mechanism by which HCMV inhibits the initial phase of monocyte apoptosis, we focused on the viral modulation of early pro-survival cell signalling events following infection. We demonstrate here that the viral upregulation of the phosphatidylinositol 3-kinase [PI(3)K] pathway promotes an early block in apoptosis following infection. Temporal transcriptome and protein analyses revealed Mcl-1, a member of the Bcl-2 family, was transiently induced in a PI(3)K-dependent manner during the early stages of HCMV infection. In accord with the survival studies, virally induced levels of Mcl-1 expression dissipated to mock levels by 72 hours post infection. Through the use of Mcl-1 specific siRNA, we confirmed the functional role that Mcl-1 plays as a key early regulator of apoptosis in monocytes. Lastly, we showed that HCMV engagement and activation of the epidermal growth factor receptor (EGFR) during viral binding triggered the upregulation of Mcl-1. Overall, our data indicates that activation of the EGFR/PI(3)K signalling pathway, via the PI(3)K-dependent upregulation of Mcl-1, is required to circumvent apoptosis in naturally short-lived monocytes during the early stages of HCMV infection, thus ensuring the early steps in the viral persistence strategy.
Related Links	http://dx.doi.org/10.4049/jimmunol.0903025
Ending Page	3222
Page Count	10
Starting Page	3213
File Format	PDF
ISSN	00221767
e-ISSN	15506606
Journal	Journal of immunology (Baltimore, Md. : 1950)
Issue Number	6
Volume Number	184
Language	English
Publisher Date	2010-03-15
Access Restriction	Open
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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