Biology Reference
In-Depth Information
setting up conditions in which the 40S ribosome subunit can recognize the mRNA
for translation (Mamane et al. 2006). Under negative growth conditions, mTORC1
is inactive and 4E-BP becomes hypophosphorylated. Hypophosphorylated 4E-BP
binds to eIF4E, retaining it from eIF4G and the eIF4F complex, thus inhibiting
cap-dependent translation.
As discussed below, mTOR kinase activity in mTORC1 is inhibited by many
cellular stress responses in order to inhibit phosphorylation of 4E-BP and cap-
dependent translation. The drug rapamycin can also do this through direct inhibi-
tion of mTOR kinase in mTORC1. It is clear that in order for HCMV to maintain
cap-dependent translation, it must find means to maintain hyperphosphorylated 4E-
BP. In other words, it needs to circumvent the effects of any cellular stress response
that might lead to the inhibition of mTOR kinase activity.
In contrast to the level of understanding of mTORC1, much less is known about
the functions of mTORC2. However, RNAi-mediated depletion of rictor in cultured
cells demonstrated that mTORC2 plays a role in actin cytoskeleton organization
(Jacinto et al. 2004; Sarbassov et al. 2004). At present the only known mTORC2
substrate is serine 473 (S473) of Akt (Sarbassov et al. 2005b; Fig. 1). The role of
S473 phosphorylation in Akt activity is controversial, but it has been suggested that
it precedes phosphorylation of T308 (the PDK1 site) and may be important for the
recognition and phosphorylation of Akt by PDK1 (Sarbassov et al. 2005b) (Fig. 1).
This suggests the potential for mTOR and Akt to be involved in an autoregulatory
loop. The control of mTORC2 activity is not well understood; however, one study
suggests that Rheb-GTP, the activator of mTORC1, does not activate mTORC2 and
may inhibit it (Yang et al. 2006b).
HCMV and the Activation of the PI3K-Akt-TSC-mTORC1
Pathway
HCMV infection has dramatic effects on the PI3K-Akt-TSC-mTORC1 pathway.
HCMV infection activates Akt through stimulation of T308 phosphorylation via
activation of PI3K (Johnson et al. 2001; Yu and Alwine 2002) and stimulation of
S473 phosphorylation via activation of mTORC2 (Kudchodkar et al. 2006) (Fig. 1).
This occurs by at least two mechanisms. First, transient activation occurs via HCMV
attachment to cell receptors which mediate signaling to PI3K (Johnson et al. 2001).
However, the identity of this receptor and the means of activating PI3K are under
debate (Isaacson et al. 2007; see the chapter by M.K. Isaacson et al., this volume).
Second, long-term activation results from the expression of HCMV encoded proteins
(Yu and Alwine 2002; Kudchodkar et al. 2006); for example, transfection experi-
ments have shown that expression of the individual major immediate early proteins
(either the 72-kDa IE1 or the 86-kDa IE2 proteins) can stimulate phosphorylation of
Akt at both sites (Yu and Alwine 2002; Y. Yu and J.C. Alwine, unpublished data).
The HCMV-induced activation of Akt leads to the activation of mTORC1, as
indicated by phosphorylation of 4E-BP and S6K, beginning 8-12 h postinfection
