Mechanisms of human cytomegalovirus infection with a focus on epidermal growth factor receptor interactions

2017 ◽  
Vol 27 (6) ◽  
pp. e1955 ◽  
Author(s):  
Aline Semblano Carreira Falcão ◽  
Pedro Fernando da Costa Vasconcelos ◽  
Dorotéa de Fátima Lobato da Silva ◽  
João de Jesus Viana Pinheiro ◽  
Luiz Fábio Magno Falcão ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Human Cytomegalovirus ◽  
Cytomegalovirus Infection ◽  
Growth Factor Receptor ◽  
Receptor Interactions ◽  
Epidermal Growth ◽  
Human Cytomegalovirus Infection

scholarly journals Inhibition of epidermal growth factor receptor (EGFR) expression by human cytomegalovirus correlates with an increase in the expression and binding of Wilms' Tumour 1 protein to the EGFR promoter

2009 ◽  
Vol 90 (7) ◽  
pp. 1569-1574 ◽  
Author(s):  
Insiya Jafferji ◽  
Mark Bain ◽  
Christine King ◽  
John H. Sinclair
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Human Cytomegalovirus ◽  
Growth Factor Receptor ◽  
Cell Surface Receptor ◽  
Wilms Tumour ◽  
Promote Cell Proliferation ◽  
Egfr Expression ◽  
Epidermal Growth

Infection with human cytomegalovirus (HCMV) modulates the expression of a number of cellular receptors and is known to inhibit expression of the epidermal growth factor receptor (EGFR), a cell surface receptor that can promote cell proliferation through a cascade of intracellular signalling events. We have examined the mechanisms by which HCMV mediates downregulation of EGFR expression and show that virus infection results in the profound upregulation of Wilms' Tumour 1 (WT1) protein, a transcription factor associated with the negative regulation of a number of growth factors and growth factor receptors, including EGFR. Moreover, chromatin immunoprecipitation experiments also show that HCMV infection results in increased binding of WT1 to the EGFR promoter. Finally, we show that depleting the cell of WT1 using small interfering RNA abrogates virus-mediated downregulation of EGFR. Taken together, our observations suggest that HCMV-mediated repression of EGFR expression results from a virus-mediated increase in cellular WT1, a known pleiotropic regulator of mitogenesis, apoptosis and differentiation.

scholarly journals PI3K-Dependent Upregulation of Mcl-1 by Human Cytomegalovirus Is Mediated by Epidermal Growth Factor Receptor and Inhibits Apoptosis in Short-Lived Monocytes

2010 ◽  
Vol 184 (6) ◽  
pp. 3213-3222 ◽  
Author(s):  
Gary Chan ◽  
Maciej T. Nogalski ◽  
Gretchen L. Bentz ◽  
M. Shane Smith ◽  
Alexander Parmater ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Human Cytomegalovirus ◽  
Growth Factor Receptor ◽  
Epidermal Growth

Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus

Nature ◽  
2003 ◽  
Vol 424 (6947) ◽  
pp. 456-461 ◽  
Author(s):  
Xin Wang ◽  
Shu-Mei Huong ◽  
Marie L. Chiu ◽  
Nancy Raab-Traub ◽  
Eng-Shang Huang
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Human Cytomegalovirus ◽  
Growth Factor Receptor ◽  
Cellular Receptor ◽  
Epidermal Growth

Real-Time Kinetics of Ligand/Cell Surface Receptor Interactions in Living Cells:  Binding of Epidermal Growth Factor to the Epidermal Growth Factor Receptor†

Biochemistry ◽  
2001 ◽  
Vol 40 (34) ◽  
pp. 10230-10242 ◽  
Author(s):  
John C. Wilkinson ◽  
Richard A. Stein ◽  
Cheryl A. Guyer ◽  
Joseph M. Beechem ◽  
James V. Staros
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Living Cells ◽  
Cell Surface Receptor ◽  
Receptor Interactions ◽  
Surface Receptor ◽  
Epidermal Growth ◽  
Kinetics Of

scholarly journals Human Cytomegalovirus Utilizes a Nontraditional Signal Transducer and Activator of Transcription 1 Activation Cascade via Signaling through Epidermal Growth Factor Receptor and Integrins To Efficiently Promote the Motility, Differentiation, and Polarization of Infected Monocytes

2017 ◽  
Vol 91 (24) ◽  
Author(s):  
Donna Collins-McMillen ◽  
Emily V. Stevenson ◽  
Jung Heon Kim ◽  
Byeong-Jae Lee ◽  
Stephen J. Cieply ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Gene Product ◽  
Human Cytomegalovirus ◽  
Growth Factor Receptor ◽  
Signal Transducer ◽  
Viral Spread ◽  
M1 Macrophage ◽  
Epidermal Growth

ABSTRACT Human cytomegalovirus (HCMV) infects peripheral blood monocytes and triggers biological changes that promote viral dissemination and persistence. We have shown that HCMV induces a proinflammatory state in infected monocytes, resulting in enhanced monocyte motility and transendothelial migration, prolonged monocyte survival, and differentiation toward a long-lived M1-like macrophage phenotype. Our data indicate that HCMV triggers these changes, in the absence of de novo viral gene expression and replication, through engagement and activation of epidermal growth factor receptor (EGFR) and integrins on the surface of monocytes. We previously identified that HCMV induces the upregulation of multiple proinflammatory gene ontologies, with the interferon-associated gene ontology exhibiting the highest percentage of upregulated genes. However, the function of the HCMV-induced interferon (IFN)-stimulated genes (ISGs) in infected monocytes remained unclear. We now show that HCMV induces the enhanced expression and activation of a key ISG transcriptional regulator, signal transducer and activator of transcription (STAT1), via an IFN-independent but EGFR- and integrin-dependent signaling pathway. Furthermore, we identified a biphasic activation of STAT1 that likely promotes two distinct phases of STAT1-mediated transcriptional activity. Moreover, our data show that STAT1 is required for efficient early HCMV-induced enhanced monocyte motility and later for HCMV-induced monocyte-to-macrophage differentiation and for the regulation of macrophage polarization, suggesting that STAT1 may serve as a molecular convergence point linking the biological changes that occur at early and later times postinfection. Taken together, our results suggest that HCMV reroutes the biphasic activation of a traditionally antiviral gene product through an EGFR- and integrin-dependent pathway in order to help promote the proviral activation and polarization of infected monocytes. IMPORTANCE HCMV promotes multiple functional changes in infected monocytes that are required for viral spread and persistence, including their enhanced motility and differentiation/polarization toward a proinflammatory M1 macrophage. We now show that HCMV utilizes the traditionally IFN-associated gene product, STAT1, to promote these changes. Our data suggest that HCMV utilizes EGFR- and integrin-dependent (but IFN-independent) signaling pathways to induce STAT1 activation, which may allow the virus to specifically dictate the biological activity of STAT1 during infection. Our data indicate that HCMV utilizes two phases of STAT1 activation, which we argue molecularly links the biological changes that occur following initial binding to those that continue to occur days to weeks following infection. Furthermore, our findings may highlight a unique mechanism for how HCMV avoids the antiviral response during infection by hijacking the function of a critical component of the IFN response pathway.

scholarly journals Human Cytomegalovirus UL135 Interacts with Host Adaptor Proteins To Regulate Epidermal Growth Factor Receptor and Reactivation from Latency

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
Michael A. Rak ◽  
Jason Buehler ◽  
Sebastian Zeltzer ◽  
Justin Reitsma ◽  
Belen Molina ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Human Cytomegalovirus ◽  
Latent Infection ◽  
Growth Factor Receptor ◽  
Adaptor Proteins ◽  
Recombinant Viruses ◽  
Hcmv Disease ◽  
Epidermal Growth

ABSTRACTHuman cytomegalovirus, HCMV, is a betaherpesvirus that establishes a lifelong latent infection in its host that is marked by recurrent episodes of reactivation. The molecular mechanisms by which the virus and host regulate entry into and exit from latency remain poorly understood. We have previously reported thatUL135is critical for reactivation, functioning in part by overcoming suppressive effects of the latency determinantUL138. We have demonstrated a role forUL135in diminishing cell surface levels and targeting epidermal growth factor receptor (EGFR) for turnover. The attenuation of EGFR signaling promotes HCMV reactivation in combination with cellular differentiation. In this study, we sought to define the mechanisms by whichUL135functions in regulating EGFR turnover and viral reactivation. Screens to identify proteins interacting with pUL135 identified two host adaptor proteins, CIN85 and Abi-1, with overlapping activities in regulating EGFR levels in the cell. We mapped the amino acids in pUL135 necessary for interaction with Abi-1 and CIN85 and generated recombinant viruses expressing variants of pUL135 that do not interact with CIN85 or Abi-1. These recombinant viruses replicate in fibroblasts but are defective for reactivation in an experimental model for latency using primary CD34+hematopoietic progenitor cells (HPCs). TheseUL135variants have altered trafficking of EGFR and are defective in targeting EGFR for turnover. These studies demonstrate a requirement for pUL135 interactions with Abi-1 and CIN85 for regulation of EGFR and mechanistically link the regulation of EGFR to reactivation.IMPORTANCEHuman cytomegalovirus (HCMV) establishes a lifelong latent infection in the human host. While the infection is typically asymptomatic in healthy individuals, HCMV infection poses life-threatening disease risk in immunocompromised individuals and is the leading cause of birth defects. Understanding how HCMV controls the lifelong latent infection and reactivation of replication from latency is critical to developing strategies to control HCMV disease. Here, we identify the host factors targeted by a viral protein that is required for reactivation. We define the importance of this virus-host interaction in reactivation from latency, providing new insights into the molecular underpinnings of HCMV latency and reactivation.

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