Biology Reference
In-Depth Information
2007). However, this mechanism seems to be of marginal effectiveness since it is
overwhelmed by the extensive phosphorylation of AMPK caused by the addition of
AICAR. However, under conditions of high levels of phosphorylated AMPK,
HCMV inhibits its downstream effects by inactivating the TSC. It has been shown
that the HCMV protein pUL38 binds to and inactivates the TSC (N.J. Moorman
et al., personal communication), thus protecting mTORC1 from inhibition. This
function of pUL38, an early protein, may explain why mTORC1-mediated phos-
phorylation of 4E-BP and S6K became resistant to the effects of AICAR by 12 h
p.i. It is important to note that the inhibition of the TSC by pUL38 may not only
block the effects of activated AMPK, but also the effects of other stress responses
such as hypoxia that function through activating the TSC.
One question that arises is why would HCMV maintain a limited ability to
dephosphorylate AMPK as well as inhibit the TSC with pUL38? It would seem
that the inhibition of the TSC would be sufficient to protect mTORC1 from
inactivation caused by AMPK activity. A putative answer arises from the obser-
vation that HCMV strives to maintain beneficial aspects of cellular stress
responses while inhibiting disadvantageous ones. The beneficial aspects of hav-
ing phosphorylated, activated AMPK are that it activates pathways that
increase: (1) ATP production, (2) glucose transport and glycolysis, and (3) fatty
acid oxidation (Luo et al. 2005). Thus, HCMV's limited ability to dephosphor-
ylate AMPK may provide a situation where some activated AMPK is maintained
during infection. In this regard, data suggest that the different effects of AMPK
are activated differentially, requiring different levels of phosphorylated AMPK
(Jones et al. 2005). For example, the amount of phosphorylated AMPK needed to
increase ATP production, glucose transport, glycolysis and fatty acid oxidation is
thought to be much less than the amount needed to activate the TSC and inhibit
translation. Hence it would be to the virus's advantage to be able to maintain lev-
els of phosphorylated AMPK capable of inducing beneficial effects but below the
level needed to activate the TSC. However, under conditions where this mecha-
nism is overwhelmed, and high levels of phosphorylated AMPK accumulate, the
pUL38-mediated inhibition of the TSC would still protect mTOR kinase activ-
ity and circumvent translation inhibition.
HCMV Effects on the mTOR Complexes and Their Substrates
One might think that the inhibition of the TSC would be sufficient to assure the
maintenance of mTORC1 activity and cap-dependent translation in the infected
cell. However, HCMV infection also targets the mTOR complexes and functionally
alters them in order to maintain 4E-BP phosphorylation and cap-dependent transla-
tion. The first indication of such a mechanism was the observation that in the pres-
ence of rapamycin, which directly inhibits mTORC1, translation was maintained in
infected human fibroblasts (Kudchodkar et al. 2004). Rapamycin causes a 12- to
24-h delay in the first appearance of progeny virions when compared to a normal
