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Opposing Regulation of the EGF Receptor: A Molecular Switch Controlling Cytomegalovirus Latency and Replication
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نویسنده
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buehler j. ,zeltzer s. ,reitsma j. ,petrucelli a. ,umashankar m. ,rak m. ,zagallo p. ,schroeder j. ,terhune s. ,goodrum f.
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منبع
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plos pathogens - 2016 - دوره : 12 - شماره : 5
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چکیده
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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. © 2016 buehler et al.
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آدرس
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bio5 institute,university of arizona,tucson,az, United States, department of cellular and molecular medicine,university of arizona,tucson,az, United States, department of microbiology and molecular genetics,medical college of wisconsin,milwaukee,wi,united states,department of biology and biological engineering,california institute of technology,pasadena,ca, United States, department of immunobiology,university of arizona,tucson,az,united states,department of microbiology and immunology,university of north carolina,chapel hill,nc, United States, bio5 institute,university of arizona,tucson,az, United States, department of cellular and molecular medicine,university of arizona,tucson,az, United States, department of immunobiology,university of arizona,tucson,az, United States, bio5 institute,university of arizona,tucson,az,united states,department of molecular and cellular biology,university of arizona,tucson,az,united states,university of arizona cancer center,university of arizona,tucson,az, United States, department of microbiology and molecular genetics,medical college of wisconsin,milwaukee,wi, United States, bio5 institute,university of arizona,tucson,az,united states,department of cellular and molecular medicine,university of arizona,tucson,az,united states,department of immunobiology,university of arizona,tucson,az,united states,department of molecular and cellular biology,university of arizona,tucson,az,united states,university of arizona cancer center,university of arizona,tucson,az, United States
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Authors
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