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.

Human Cytomegalovirus Requires Epidermal Growth Factor Receptor Signaling To Enter and Initiate the Early Steps in the Establishment of Latency in CD34 + Human Progenitor Cells

“…The HCMV signalosome created by activation of EGFR and integrins also promotes extended survival of infected monocytes, allowing HCMV to overcome the biologically limited life span of monocytes (37) and to combat the antiviral proapoptotic response to HCMV infection (46). EGFR also modulates both viral replication and latency in CD34 ϩ HPCs by functioning as a molecular switch that controls the replicative state of HCMV (47). EGFR activity favors the long-term maintenance of latency in CD34 ϩ HPCs, whereas inhibition of EGFR signaling promotes reactivation and replication (47).…”

“…EGFR also modulates both viral replication and latency in CD34 ϩ HPCs by functioning as a molecular switch that controls the replicative state of HCMV (47). EGFR activity favors the long-term maintenance of latency in CD34 ϩ HPCs, whereas inhibition of EGFR signaling promotes reactivation and replication (47). Two opposing viral determinants (UL138 and UL135, important for regulating latency and reactivation, respectively) target EGFR with opposite effects on its endocytic trafficking and activity (47).…”

“…EGFR activity favors the long-term maintenance of latency in CD34 ϩ HPCs, whereas inhibition of EGFR signaling promotes reactivation and replication (47). Two opposing viral determinants (UL138 and UL135, important for regulating latency and reactivation, respectively) target EGFR with opposite effects on its endocytic trafficking and activity (47). UL138, which promotes latent infection (48,49), sequesters EGFR at the cell surface and sustains its signaling activity (47).…”

Recent advances in CMV tropism, latency, and diagnosis during aging

“…To define the mechanism by which UL135 and UL138 oppose one another, we identified viral and host proteins interacting with UL138 and UL135 proteins to begin to define the mechanisms by which these proteins function. We show that UL135 and UL138 both target the same receptor tyrosine kinase (RTK), epidermal growth factor receptor (EGFR) (Buehler et al 2016). EGFR is a major homeostatic regulator involved in cellular proliferation, differentiation, and survival, making it an ideal target for viral manipulation during infection.…”

“…Consistent with the role of UL135 in promoting replication, inhibition of EGFR or downstream phosphoinositide 3-kinase (PI3K) favors reactivation from latency and replication. We propose a model whereby UL135 and UL138 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 (Buehler et al 2016). Understanding the mechanisms by which HCMV modulates its latent cycle is critical to ultimately control latency and reactivation (Goodrum 2016).…”