Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 241

proceed. Even though autophagy is a degradation process in which the
autophagosome fuses with the lysosome to permit degradation of the
autophagosome content, ER-phagy is not a degradation process since
mutants lacking vacuolar proteases are able to sequester the ER. Thus, the
function of ER-phagy seems to involve sequestering damaged portions of
the ER, misfolded protein aggregates that cannot be degraded by other
means, as well as reducing the volume of the ER once ER stress is over
( Bernales et al., 2006 , 2007 ).
In summary, secretory proteins and most integral membrane proteins
enter into ER for proper folding and covalent modifications to assemble into
complexes of higher order. ER-resident chaperones and other modifying
enzymes assist proteins to achieve their active and final, three-dimensional
conformation. Only properly folded and assembled proteins are allowed
to exit the ER, thereby providing an exquisite quality-control mechanism
that maintains the fidelity of protein synthesis. The process is regulated at
multiple levels ensuring that ER folding capacity is not overwhelmed, thus
maintaining ER homeostasis. At the center of this regulation is the phyloge-
netically conserved process of the UPR, a key signaling pathway that trig-
gers comprehensive remodeling of the ER and the biosynthetic pathway
according to the different cellular needs. In parallel, autophagy is another
important degradation pathway normally induced by nutrient deprivation
and more recently, under ER stress conditions, to protect cells from death.
Two reports ( Bernales et al., 2006 , 2007 ) that describe the new process of
ER-phagy provide direct evidence that the ER can serve as a membrane
source for autophagosome formation. Further, they indicate that this pro-
cess entails engulfment of the ER by itself, targeting the ER as the major
organelle involved in the regulation of cellular component degradation. As
such, it plays an important role in protein- and organelle-degradation func-
tionality of the ER critical to homeostatic cellular control.
5. UPR AND CELL METABOLISM
The main goal of the UPR is to restore the equilibrium between
protein load and folding capacity of the ER. From a metabolic point of
view, protein folding in the ER is a demanding process, due to its high-
energy requirements ( Fig. 5.4 ). For example, saccharides are needed for
the N-glycosylation of client proteins, reductive equivalents are consumed
in the formation of disulphide bonds and an appropriate supply of ATP is
essential for calcium accumulation in the ER and chaperone activity.