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a direct mechanism and contact between both organelles is the nonvesicular
transport of phosphatidylinositol and diacylglycerol, which also depends
on VAP, and, in the case of phosphatidylinositol, requires the Nir2 protein
( Peretti et al., 2008 ).
As noted above, regulation of Ca 2+ by the ER is a key component of cel-
lular signaling, adaptation and survival. Additionally, the ER has been impli-
cated in a complex communication system with other organelles, including
the Golgi apparatus, the plasma membrane, the nucleus, and mitochondria.
The next sections of this review will focus on these communication pro-
cesses, particularly, on the ability of ER Ca 2+ signals to modulate cellular
bioenergetics, thereby influencing cellular metabolism during stress and
survival.
3. ER STRESS AND UNFOLDED PROTEIN RESPONSE
3.1. General Aspects of the UPR
Conditions that alter ER homeostasis and proper ER functioning gener-
ate a state known as ER stress . Many different factors may lead to this state,
which can be very detrimental to cell integrity, due to accumulation of
toxic, unfolded proteins within the ER lumen. For this reason, restoring ER
homeostasis is essential for cell survival. Cells subject to ER stress activate
a series of processes, which, if insufficient to alleviate the stress, lead to cell
death.
The cellular response to ER stress is known as the unfolded protein
response (UPR). In principle, the UPR seeks to restore the normal func-
tioning of the ER, using multiple strategies acting in parallel and in series.
For example, expression of ER chaperone proteins increases to prevent
protein aggregation and facilitate correct protein folding. Also, the amount
of protein in transit through the ER is reduced by temporary inhibition
of protein translation. Furthermore, ER volume increases by stimulating
the synthesis of membrane lipids. Finally, degradation of unfolded proteins
increases by activating the process of endoplasmic reticulum-associated pro-
tein degradation (ERAD).
During UPR, perturbations in ER homeostasis are sensed and trans-
duced to the cytoplasm and nucleus causing a compensatory response.
Several ER stress sensors are involved, all of which harbor luminal, trans-
membrane and cytoplasmic domains. Any increase in the concentration of
misfolded proteins is detected by the luminal sensor domain and then trans-
duced to the cytoplasm and nucleus, through different signals ( Fig. 5.2 ).
 
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