title: Opposing Regulation of the EGF Receptor: A Molecular Switch Controlling Cytomegalovirus Latency and Replication.
abstract: 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.
authors.affiliation: BIO5 Institute, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Jason
authors.identifier: 0000-0002-0116-0044
authors.initials: J
authors.lastname: Buehler
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zeltzer
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Justin
authors.initials: J
authors.lastname: Reitsma
authors.affiliation: Department of Immunobiology, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Alex
authors.initials: A
authors.lastname: Petrucelli
authors.affiliation: BIO5 Institute, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Mahadevaiah
authors.initials: M
authors.lastname: Umashankar
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Mike
authors.initials: M
authors.lastname: Rak
authors.affiliation: Department of Immunobiology, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Patricia
authors.initials: P
authors.lastname: Zagallo
authors.affiliation: BIO5 Institute, University of Arizona, Tucson, Arizona, United States of America.|Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, United States of America.|University of Arizona Cancer Center, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Joyce
authors.initials: J
authors.lastname: Schroeder
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
authors.forename: Scott
authors.initials: S
authors.lastname: Terhune
authors.affiliation: BIO5 Institute, University of Arizona, Tucson, Arizona, United States of America.|Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona, United States of America.|Department of Immunobiology, University of Arizona, Tucson, Arizona, United States of America.|Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona, United States of America.|University of Arizona Cancer Center, University of Arizona, Tucson, Arizona, United States of America.
authors.forename: Felicia
authors.initials: F
authors.lastname: Goodrum
mesh_terms: D002460:Cell Line; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D021381:Protein Transport; D017735:Virus Latency / Q000502:physiology*; D014779:Virus Replication / Q000502:physiology*
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors