Date Published: May 24, 2016
Publisher: Public Library of Science
Author(s): Jason Buehler, Sebastian Zeltzer, Justin Reitsma, Alex Petrucelli, Mahadevaiah Umashankar, Mike Rak, Patricia Zagallo, Joyce Schroeder, Scott Terhune, Felicia Goodrum, Andrew Yurochko.
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.
Human cytomegalovirus (CMV), a β-herpesvirus ubiquitous in the world’s population, has adapted many trade-offs for its persistence. CMV replicates to low titers and causes minimal cytopathology, such that the primary infection is typically unapparent. CMV, like all herpesviruses, persists in the host through the establishment of latent state and chronic states . During latency, CMV genomes are maintained in the infected cell with little to no viral gene expression and no virus replication. Given the commitment of T-cell immunity to CMV infection , CMV likely reactivates subclinically with high frequency. However, in an immune incompetent host, including solid organ or stem cell transplant recipients, CMV reactivation remains a major cause of morbidity and mortality . There is no CMV vaccine, and current antivirals fail to target the latent virus. Understanding the mechanistic basis of latency is critical to developing strategies to target latent virus.
Herpesviruses have evolved complex interactions with the host to achieve lifelong persistence. To avoid elimination, herpesviruses masterfully evade intrinsic, innate and adaptive defenses to infection. Although less well defined, herpesviruses also modulate epigenetic silencing and homeostatic signaling in the host cell to create an optimal environment for persistence. EGFR is a major homeostatic regulator of cell proliferation, differentiation, adhesion/migration, survival [36, 37], and most recently, innate signaling [38, 39] and DNA repair . As such, EGFR represents a potentially powerful target for viral manipulation during infection with complex DNA viruses.