Endoplasmic Reticulum and the Unfolded Protein Response: Dynamics and Metabolic Integration - International Review of Cell and Molecular Biology - page 235

The PERK pathway is also linked to IRE1α and ATF6. Recently, a
dominant negative form of PERK was shown to activate ATF6 and XBP1
( Yamaguchi et al., 2008 ). However, in another study, PERK was shown to
facilitate both the synthesis and trafficking of ATF6 from the ER to the
Golgi ( Teske et al., 2011 ). All these studies underscore the notion that indi-
vidual branches of the UPR are connected in ways that permit generating
integrated responses to stress. Also, such connectivity explains the diverse
defects associated with loss of any one of the sensors.
The integrated responses elicited by the three ER stress sensors con-
tribute to either adaptation or death, but it remains unknown how each
branch contributes to the final biological effect. A number of studies have
attempted to resolve this issue. For instance, IRE1 and ATF6 activities are
attenuated by persistent ER stress, while PERK signaling is not ( Lin et al.,
2007 ). Indeed, sustained PERK signaling impairs cell proliferation and pro-
motes apoptosis. By contrast, signaling via IRE1α for an equivalent period
of time enhances cell proliferation without promoting cell death ( Lin et al.,
2009 ), suggesting that the differential activation of PERK and IRE1α may
determine cell fate following ER stress.
4. ENDOPLASMIC RETICULUM AND PROTEIN
DEGRADATION
4.1. Endoplasmic Reticulum Quality Control
One of the main functions of the ER is the synthesis of proteins targeted to
the secretory pathway. Proteins synthesized in the ER develop the appro-
priately folded native conformation following posttranslational modifica-
tions such as N-glycosylation and the formation of disulfide bonds. In order
to export only correctly folded proteins, the ER is home to a variety of
chaperones which facilitate protein folding. At the same time, they function
as part of a quality-control system, which ensures that incompletely folded
proteins are retained in the ER or targeted to degradation if appropriate
folding cannot be achieved ( Fig. 5.3 ).
The lectins calnexin and calreticulin play essential roles as chaperones
in the ER quality-control system. As previously mentioned, most nascent
polypeptide chains in the ER are N-glycosylated to facilitate the folding
process ( Schröder, 2008 ). Upon N-glycosylation, a branched oligosac-
charide is attached to an asparagine residue on the target protein, thereby
increasing the hydrophilicity of the nascent protein. Calnexin and calre-
ticulin bind to glycosylated substrates containing a terminal glucose residue