Biology Reference
In-Depth Information
Modulation of Host Cell Stress Responses
by Human Cytomegalovirus
J. C. Alwine
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264
Background: PI3K-Akt-TSC-mTOR Signaling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265
Background: The Complexes of mTOR Kinase and Their Activities. . . . . . . . . . . . . . . . . . . 266
HCMV and the Activation of the PI3K-Akt-TSC-mTORC1 Pathway . . . . . . . . . . . . . . . . . . 268
Hypoxia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
Energy Depletion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
Amino Acid Depletion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
Rapamycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
The Effects of HCMV Downstream of Akt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
HCMV Effects on the mTOR Complexes and Their Substrates. . . . . . . . . . . . . . . . . . . . . . . 272
HCMV Effects on eIF4E and Mnk-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
Conclusions, Questions, Speculations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Abstract
Human cytomegalovirus (HCMV) induces cellular stress responses during
infection due to nutrient depletion, energy depletion, hypoxia and synthetic stress,
e.g., endoplasmic reticulum (ER) stress. Cellular stress responses initiate processes
that allow the cell to survive the stress; some of these may be beneficial to HCMV
replication while others are not. Several studies show that HCMV manipulates stress
response signaling in order to maintain beneficial effects while inhibiting detrimental
effects. The inhibition of translation is the most common effect of stress responses
that would be detrimental to HCMV infection. This chapter will focus on the mecha-
nisms by which cap-dependent translation is maintained during HCMV infection
through alterations of the phosphatidylinositol-3′ kinase (PI3K)-Akt-tuberous scle-
rosis complex (TSC)-mammalian target of rapamycin (mTOR) signaling pathway.
The emerging picture is that HCMV affects this pathway in multiple ways, thus
J.C. Alwine
Department of Cancer Biology and the Abramson Family Cancer Research Institute,
University of Pennsylvania, 314 Biomedical Research Building, 421 Curie Blvd. Philadelphia ,
PA 19104-6142 , USA
alwine@mail.med.upenn.edu
