Biology Reference
In-Depth Information
ensuring that cap-dependent translation is maintained despite the induction of stress
responses that would normally inhibit it. Such dramatic alterations of this pathway
lead to questions of what other beneficial effects the virus might gain from these
changes and how these changes may contribute to HCMV pathogenesis.
Abbreviations 4E-BP : eIF4E binding protein; AICAR: 5-Amino-4-imidazole-
carboxamide ribose; Akt: The cellular homolog of the oncoprotein of the AKT8
retrovirus ; AMPK : AMP-activated kinase ; CaMKKβ : Calcium/calmodulin-dependent
protein kinase kinase-β ; ER : Endoplasmic reticulum ; eIF : Eucaryotic initiation
factor ; FKBP12 : FK506 binding protein ; HCMV : Human cytomegalovirus ; IR :
Insulin receptor; IRS: Insulin receptor substrates; mTOR: Mammalian target of
rapamycin ; mTORC1 : mTOR complex 1 ; mTORC2 : mTOR complex 2 ; PDK1 :
Phosphainositide-dependent protein kinase-1; PI3K: Phosphatidylinositol-3′ kinase;
PIP2 : Phosphatidylinositol-4,5-bisphosphate ; PIP3 : Phosphatidylinositol-3,4,5-
triphosphate ; PP2A : Protein phosphatase 2A ; PTEN : Phosphatase and tensin homolog ;
S6K : p70S6 Kinase ; TSC : Tuberous sclerosis complex
Introduction
Human cytomegalovirus (HCMV) shares a general life cycle strategy with other
mammalian double-stranded DNA viruses that replicate in the nucleus: it must
adapt the cellular milieu so the host cell can accommodate the increased demand
for nutrients, energy and macromolecular synthesis that accompanies viral infection.
For example, successful viral replication requires (1) increased glucose uptake,
metabolism and oxygen utilization; (2) abrogation of cellular growth controls;
(3) manipulation of the cell cycle to a point that is optimal for virus growth; and (4)
inhibition of apoptosis during the productive phase of replication.
These massive changes in the cell's physiology induce cellular stress responses,
due to nutrient depletion, energy depletion, hypoxia and synthetic stress, e.g., endo-
plasmic reticulum (ER) stress. Cellular stress responses are designed to signal the
cell when it is in potential trouble and initiate conditions to allow the cell to survive
the stress. As a last resort, when the efforts to abate stress fail, apoptosis is induced.
Stress responses have many effects on cellular processes; among these some may
be beneficial to HCMV replication while others may not. Existing data suggest that
HCMV may be able to manipulate stress responses in order to maintain beneficial
effects while inhibiting detrimental effects (Isler et al. 2005b; Hakki et al. 2006).
Inhibition of translation is among the most common consequences of cellular stress
responses (Kaufman et al. 2002; Arsham et al. 2003; Holcik and Sonenberg 2005;
Wouters et al. 2005; Wek et al. 2006). Since translation is an energy-intensive process,
its inhibition results in decreased demand for ATP/GTP and decreases the load of pro-
teins entering the ER for processing, consequently relieving ER stress. Translation is
well suited to respond to stress, since its inhibition can be accomplished rapidly and
reversibly by altering the phosphorylation state of translation regulatory proteins.
For example, cap-dependent translation, in which translation initiation depends on
Search WWH ::




Custom Search