Modulation of Host Cell Stress Responses by Human Cytomegalovirus - Human Cytomegalovirus - page 263

Fig. 3 The effects of stress inducers and HCMV infection on the PI3K-Akt-mTOR pathway, its
associated substrates and the components of the eIF4F complex. Stress inducers ( green ) are shown
at sites where they affect the PI3K-Akt-mTOR pathway. The points shown in red indicate where
HCMV infection exerts its effects; Table 1 presents a synopsis of each, see text for details
(Kudchodkar et al. 2004). Although Akt activation is necessary to maintain
cap-dependent translation, it is not sufficient. The virus must do more since mTOR
kinase activity can be inhibited by many stress responses which exert their effects
at points downstream of Akt in the signaling pathway (Fig. 3). Stress responses that
do this are induced by the following conditions:
Hypoxia
Hypoxia may occur during the highest rates of metabolic and synthetic activity in
HCMV-infected cells. Hypoxia inhibits mTORC1 (Arsham et al. 2002; Brugarolas
et al. 2004; Cai et al. 2006) due to the induction of REDD1 (Brugarolas et al. 2004), a
protein which activates the TSC (reviewed in van den Beucken et al. 2006). This mecha-
nism is dependent on the induction of hypoxia inducing factor-1 (HIF-1), since the
redd1 gene is a HIF-1 transcriptional target (Schwarzer et al. 2005). A HIF-independent
oxygen sensing mechanisms for activation of the TSC involves activation of the AMP-
activated kinase (AMPK, Figs. 1 and 3) (Corradetti et al. 2004; Shaw et al. 2004).