Biology Reference
In-Depth Information
eIF4E by Mnk-1 is enhanced to maintain translation; moreover, the levels of eIF4E
are increased in infected cells (Walsh et al. 2005). Increasing the amount of eIF4E
would be predicted to titrate out hypophosphorylated 4E-BP while still maintaining
sufficient free eIF4E to bind eIF4G and preserve the integrity of the eIF4F complex.
This is again a situation where HCMV appears to use redundant mechanisms: (1)
hyperphosphorylation of 4E-BP to lower its affinity for eIF4E and (2) increased
levels of eIF4E to titrate out hypophosphorylated 4E-BP. Such redundancy indi-
cates the importance of maintaining cap-dependent translation during HCMV
infection. In addition, the two different mechanisms may be required to maintain
cap-dependent translation in different cell types and under different growth
conditions.
Conclusions, Questions, Speculations
The points shown in red in Fig. 3 indicate where HCMV infection exerts its effects
on the PI3K-Akt-TSC-mTOR pathway, its associated substrates and the components
of the eIF4F complex; Table 1 presents a synopsis of each. The striking feature is
the number of ways the virus has evolved to manipulate this pathway and thereby
manipulate the effects of cellular stress responses. The effects of stress responses
that would be inhibitory to viral growth are circumvented, while potentially beneficial
effects may be maintained. It is also striking that in more than one case the virus
has introduced multiple means to circumvent inhibitory effects of stress responses:
for example, the phosphorylation of 4E-BP plus the increased levels of eIF4E and
the inhibition of the TSC plus the dephosphorylation of AMPK. The maintenance
of redundant mechanisms suggests that they provide the virus with additional
capabilities yet to be discovered and understood.
Table 1
Effects of HCMV infection on the PI3K-Akt-TSC-mTOR pathway, its associated sub-
strates and the components of the eIF4F complex
Target
HCMV-mediated mechanism
PI3K
Activated by viral attachment, MIEPs and possible other viral or induced
cellular proteins
Akt
Phosphorylated by HCMV activated PI3K-PDK1 and mTORC2
AMPK
Inactivated by dephosphorylation
TSC
Inactivated by HCMV UL38
mTORC1
Activated by HCMV infection
Altered producing rapamycin insensitivity
mTORC2
Activated by HCMV infection
Altered producing rapamycin sensitivity and gaining 4E-BP and
S6K as substrates
eIF4E
Level increased during HCMV infection
Mnk1
Phosphorylation of eIF4E increased by HCMV infection
S6
Phosphorylated by an HCMV-induced mechanism that does not involve S6K
(Kudchodkar et al. 2004)
