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Opposing Regulation of the EGF Receptor: A Molecular Switch Controlling Cytomegalovirus Latency and Replication

Buehler, Jason and Zeltzer, Sebastian and Reitsma, Justin and Petrucelli, Alex and Umashankar, Mahadevaiah and Rak, Mike and Zagallo, Patricia and Schroeder, Joyce and Terhune, Scott and Goodrum, Felicia (2016) Opposing Regulation of the EGF Receptor: A Molecular Switch Controlling Cytomegalovirus Latency and Replication. PLOS Pathogens, 12 (5). Art. No. e1005655. ISSN 1553-7374. PMCID PMC4878804.

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[img] MS Word (S1 Text. Expanded experimental design and supplemental data results) - Supplemental Material
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[img] Image (TIFF) (S1 Table. EGFR and EGFR-associated proteins interacting with HCMV pUL138 during lytic infection) - Supplemental Material
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[img] Image (TIFF) (S1 Fig. pUL138 increases TNFR cell surface levels) - Supplemental Material
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[img] Image (TIFF) (S2 Fig. Activated EGFR localizes to the viral assembly compartment during UL135_(STOP) and UL138_(STOP) infection) - Supplemental Material
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[img] Image (TIFF) (S3 Fig. Conjugated EGF ligand has increased sensitivity for detection of surface EGFR) - Supplemental Material
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[img] Image (TIFF) (S4 Fig. Inhibition of EGFR with Gefitinib promotes reactivation from latency) - Supplemental Material
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Herpesviruses persist indefinitely in their host through complex and poorly defined interactions that mediate latent, chronic or productive states of infection. Human cytomegalovirus (CMV or HCMV), a ubiquitous β-herpesvirus, coordinates the expression of two viral genes, UL135 and UL138, which have opposing roles in regulating viral replication. UL135 promotes reactivation from latency and virus replication, in part, by overcoming replication-suppressive effects of UL138. The mechanism by which UL135 and UL138 oppose one another is not known. We identified viral and host proteins interacting with UL138 protein (pUL138) to begin to define the mechanisms by which pUL135 and pUL138 function. We show that pUL135 and pUL138 regulate the viral cycle by targeting that same receptor tyrosine kinase (RTK) epidermal growth factor receptor (EGFR). EGFR is a major homeostatic regulator involved in cellular proliferation, differentiation, and survival, making it an ideal target for viral manipulation during infection. pUL135 promotes internalization and turnover of EGFR from the cell surface, whereas pUL138 preserves surface expression and activation of EGFR. We show that activated EGFR is sequestered within the infection-induced, juxtanuclear viral assembly compartment and is unresponsive to stress. Intriguingly, these findings suggest that CMV insulates active EGFR in the cell and that pUL135 and pUL138 function to fine-tune EGFR levels at the cell surface to allow the infected cell to respond to extracellular cues. Consistent with the role of pUL135 in promoting replication, inhibition of EGFR or the downstream phosphoinositide 3-kinase (PI3K) favors reactivation from latency and replication. We propose a model whereby pUL135 and pUL138 together with EGFR comprise a molecular switch that regulates states of latency and replication in HCMV infection by regulating EGFR trafficking to fine tune EGFR signaling.

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Additional Information:© 2016 Buehler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: December 2, 2015; Accepted: May 2, 2016; Published: May 24, 2016. Editor: Andrew Yurochko, Louisiana State University Health Sciences Center, UNITED STATES. We acknowledge Dr. Jean Wilson at the University of Arizona for helpful discussion and critical reading of the manuscript. We acknowledge Paul Campbell and the Arizona Cancer Center/Arizona Research Laboratories Division of Biotechnology Cytometry Core Facility for expertise and assistance in flow cytometry and Patricia Jansma of the Molecular and Cellular Biology Imaging Facility for expertise in and assistance in fluorescent imaging. Special thanks to Terry Fox Laboratory for providing the M2-10B4 and Sl/Sl cells. We acknowledge Drs. Tom Shenk and Michael Nevels for the gift of antibodies. Author Contributions: Conceived and designed the experiments: JB SZ JR MU MR AP PZ JS ST FG. Performed the experiments: JB SZ JR MU MR AP PZ. Analyzed the data: JB SZ JR MU PZ ST FG. Contributed reagents/materials/analysis tools: JS ST. Wrote the paper: JB FG. Data Availability: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by Public Health Service Grants AI079059 and AI105062 (to FG) and AI083281 (to ST) from the National Institute of Allergy and Infectious Disease ( and Cancer Center Support Grant P30CA023074. FG is a 2008 Pew Scholar in the Biomedical Sciences, supported by the Pew Charitable Trusts ( JB was supported by a National Cancer Institute Training Grant T32 CA009213 ( The funders had no role in the study design, data collection, analysis, decision to publish or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist.
Funding AgencyGrant Number
Pew Charitable TrustUNSPECIFIED
NIH Predoctoral FellowshipT32 CA009213
Issue or Number:5
PubMed Central ID:PMC4878804
Record Number:CaltechAUTHORS:20160729-125721865
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Official Citation:Buehler J, Zeltzer S, Reitsma J, Petrucelli A, Umashankar M, Rak M, et al. (2016) Opposing Regulation of the EGF Receptor: A Molecular Switch Controlling Cytomegalovirus Latency and Replication. PLoS Pathog 12(5): e1005655. doi:10.1371/journal.ppat.1005655
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:69319
Deposited By: George Porter
Deposited On:29 Jul 2016 21:35
Last Modified:03 Oct 2019 10:21

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