Biology Reference
In-Depth Information
Glycoprotein-mediated signaling is not the only tool in the virion arsenal, as the
virion has evolved a mechanism to capture cellular signal modifying enzymes
(Michelson et al. 1996; Gallina et al. 1999; Nogalski et al. 2007), which can be
dumped directly into the cytosol following viral entry into host cells. In addition,
like all herpesviruses, HCMV has a large number of tegument proteins that modu-
late cellular signaling (Mocarski et al. 2007). Lastly, viral gene products synthesized
following infection can also manipulate host cellular responses (some examples
include IE proteins that alter the cell cycle and regulate apoptosis (reviewed in
Castillo and Kowalik 2004; Andoniou and Degli-Esposti 2006) or those viral gene
products that mimic cellular cytokine/chemokine signaling receptors including
US28 (reviewed in Streblow et al. 2001b; Stropes and Miller 2004; van Cleef et al.
2006), a viral G protein-coupled receptor (GPCR), and UL144 (Benedict et al.
1999; Poole et al. 2006), a tumor necrosis factor-like receptor. Together, it is evi-
dent that HCMV possesses an array of signal-modifying capabilities that are
deployed over a temporal range during the infection process. The likely outcome of
this viral-mediated signaling is currently under debate. We suggest the viral-mediated
cellular modification is required for multiple critical steps in the viral infection
cycle and that the viral-directed signaling can have different outcomes in different
cell types. In fibroblasts, for example, the initial signaling seen following receptor/
ligand engagement is reported to promote viral entry (Wang et al. 2003; Feire et al.
2004; Wang et al. 2005) and then productive infection by promoting efficient gene
transcription (Caposio et al. 2004; DeMeritt et al. 2004, 2006; DeMeritt and
Yurochko 2006). In other cell types such as endothelial cells (Bentz et al. 2006) and
monocytes (Smith et al. 2004b, 2007), viral-mediated signaling can stimulate
the functional changes in these cells required for hematogenous dissemination of
the virus. Below we provide a more detailed overview of these different viral-
directed steps controlling signaling.
Receptor/Ligand-Mediated Signaling: Viral Glycoproteins
Envelope glycoproteins play an essential role in viral attachment and entry (Britt
and Mach 1996; Mocarski et al. 2007; see the chapter by
.K. Isaacson et al., this
volume). From a signaling standpoint, these molecules are logical players in the
rapid manipulation of the host cell because they are the first viral molecules to
contact a target cell. Although HCMV encodes a number of envelope glycoproteins
(Britt and Mach 1996; Mocarski et al. 2007), glycoprotein B (gB/UL55; Britt and
Mach 1996) and glycoprotein H (gH/UL75 and its associated partners gL/UL115,
gO/UL74, and the UL131-UL128 loci; Britt and Mach 1996; Hahn et al. 2004;
Wang and Shenk 2005a, b; Patrone et al. 2007) are the glycoproteins documented
to be bona fide signaling molecules (Keay et al. 1995; Yurochko et al. 1997a; Boyle
et al. 1999; Yurochko and Huang 1999; Simmen et al. 2001; Compton et al. 2003;
Wang et al. 2003, 2005; Boehme et al. 2004, 2006; Feire et al. 2004). The gH com-
plex was originally shown to stimulate calcium flux (Keay et al. 1995), while we
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