Human Cytomegalovirus Glycoprotein-Initiated Signaling Mediates the Aberrant Activation of Akt

Abstract

Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality among immunocompromised and immunonaive individuals. HCMV-induced signaling initiated during viral entry stimulates a rapid noncanonical activation of Akt to drive the differentiation of short-lived monocytes into long-lived macrophages, which is essential for viral dissemination and persistence. We found that HCMV glycoproteins gB and gH directly bind and activate cellular epidermal growth factor receptor (EGFR) and integrin β1, respectively, to reshape canonical Akt signaling within monocytes. The remodeling of the Akt signaling network was due to the recruitment of non-traditional Akt activators to either the gB- or gH-generated receptor signaling complexes. Phosphoinositide 3-kinase (PI3K) comprised of the p110β catalytic subunit was recruited to the gB/EGFR complex despite p110δ being the primary PI3K isoform found within monocytes. Concomitantly, SH2 domain-containing inositol 5-phosphatase 1 (SHIP1) was recruited to the gH/integrin β1 complex, which is critical to aberrant Akt activation as SHIP1 diverts PI3K signaling towards a noncanonical pathway. Although integrin β1 was required for SHIP1 recruitment, gB-activated EGFR mediated SHIP1 activation, underscoring the importance of the interplay between gB- and gH-mediated signaling to the unique activation of Akt during HCMV infection. Indeed, SHIP1 activation mediated the increased expression of Mcl-1 and HSP27, two Akt-dependent anti-apoptotic proteins specifically upregulated during HCMV infection but not during growth factor treatment. Overall, our data indicate that HCMV glycoproteins gB and gH work in concert to initiate a HCMV-specific signalsome responsible for the atypical activation of Akt required for infected monocyte survival and ultimately viral persistence. IMPORTANCE Human cytomegalovirus (HCMV) infection is endemic throughout the world regardless of socio-economic conditions and geographic locations with a seroprevalence reaching up to 100% in some developing countries. Although asymptomatic in healthy individuals, HCMV can cause severe multi-organ disease in immunocompromised or immunonaive patients. HCMV disease is a direct consequence of monocyte-mediated systematic spread of the virus following infection. Because monocytes are short-lived cells, HCMV must subvert the natural short lifespan of these blood cells by inducing a distinct activation of Akt, a serine/theonine-protein kinase. In this work, we demonstrate that HCMV glycoproteins gB and gH work in tandem to reroute classical host cellular receptor signaling to aberrantly activate Akt and drive survival of infected monocytes. Deciphering how HCMV modulates the cellular pathway to induce monocyte survival is important to develop a new class of anti-HCMV drugs that could target and prevent spread of the virus by eliminating infected monocytes.

Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis

“…Activation of AKT induced by gB has also been demonstrated to promote monocytes survival [295,296]. Specifically, gB has been shown to act in tandem with HCMV glycoprotein H (gH) leading to atypical activation of Akt which ultimately leads to inhibition of apoptosis (Figure 5).…”

Evasion of the Host Immune Response by Betaherpesviruses

“…The simultaneous activation of EGFR and integrin β1 results in noncanonical activation of AKT signaling. Lastly, inhibition of SHIP was shown to downregulate the pro-survival proteins Mcl-1 and HSP27 [ 159 ]. This contrasts with its normal inhibitory function [ 154 ]; however, aberrant SHIP function has been previously demonstrated in cancer cells [ 160 ].…”

Human Cytomegalovirus UL7, miR-US5-1, and miR-UL112-3p Inactivation of FOXO3a Protects CD34 + Hematopoietic Progenitor Cells from Apoptosis

“…In monocytes, the binding of HCMV gB to epidermal growth factor receptor (EGFR), as well as the binding of the viral pentameric complex to integrins, drives signaling through phosphatidylinositol 3-kinase (PI3K) and mTOR kinase that leads to the upregulation of MCL-1 ( 18 ). The virus, after 48 h of infection, shifts from MCL-1 to Bcl-2 as the primary antiapoptotic tool, and the upregulation of Bcl-2 is mediated by integrin signaling events following initial viral binding ( 19 ). In CD34 + HPCs, Reeves et al showed that MCL-1 is upregulated via gB stimulation of mitogen-activated protein kinase (MAPK) signaling in the absence of de novo viral gene expression ( 20 ).…”