Biology Reference
In-Depth Information
post-entry events) to manipulate a variety of cell types. It is the goal of this chapter
to provide an overview of the diverse mechanisms HCMV employs to modulate cel-
lular signaling pathways, as well as a discussion of the likely biological rationale for
why the virus may have evolved a strategy to dysregulate host cell signaling path-
ways following infection.
Signaling Overview
HCMV infection results in a wide range of cellular changes including changes in
calcium flux and lipid metabolism, activation of kinase signaling cascades (such as
calcium/calmodulin-dependent protein kinases, multiple cell cycle-regulated
kinases, the epidermal growth factor receptor (EGFR), the IκB kinase (IKK) cas-
cade, the mammalian target of rapamycin pathway, various members of the mitogen
activated protein kinase (MAPK) pathway, the phosphatidylinositol 3-kinase
(PI(3)K) pathway, and the src family of kinases), cytoskeletal changes, activation
of cellular transcription factors (such as AP-1, ATF/CREB, E2F, NFκ-B, Sp1), the
induction of proto-oncogenes and other cellular immediate-early (IE) response
genes (reviewed in Albrecht et al. 1990, 1993; Evers et al. 2004; DeMeritt and
Yurochko 2006). Signaling-induced changes in infected cells can loosely be
grouped into two tiers (Table 1): the first tier represents changes that occur prior to
the initiation of viral gene expression and, thus, are mediated by the virion itself;
and the second tier represents those changes that occur temporally after the produc-
tion of viral gene products and, thus, are mediated by proteins from the different
temporal gene classes. The virion itself is a potent signaling player as the viral
envelope glycoproteins initiate rapid cellular responses upon binding to cognate
receptors (reviewed in Evers et al. 2004; DeMeritt and Yurochko 2006).
Table 1 Summary of viral-associated signaling a
Rapid Delayed
Modulator effects b effects b Function
Viral glycoproteins X Receptor/ligand-mediated signaling
Captured cellular enzymes X ? Activation of signaling pathways
Tegument proteins c X ? Activation of signaling pathways/
cell cycle regulation
Other viral gene products d - X Activation of signaling pathways/
cell cycle regulation
a Individual gene products are discussed in the text
b Signaling induced upon HCMV infection can loosely be grouped into the products that regulate
rapid responses (beginning within minutes of infection) and are caused by modulators associated
with the virion vs those products that regulate effects later in infection (or delayed compared to
the rapid effects) and are caused by viral gene products de novo synthesized following infection
c Tegument proteins or tegument-associated virion proteins are included together
d Other viral gene products in this table represent those gene products that are synthesized de novo
in the infected cell and are not attributed to virion mediated signaling
 
Search WWH ::




Custom Search