The endoplasmic reticulum (ER) is the site where proteins enter the secretory pathway.
Proteins are translocated into the ER lumen in an unfolded state and require protein
chaperones and catalysts of protein folding to attain their final appropriate conformation.
A sensitive surveillance mechanism exists to prevent misfolded proteins from transiting
the secretory pathway and ensures that persistently misfolded proteins are directed
towards a degradative pathway. In addition, those processes that prevent accumulation
of unfolded proteins in the ER lumen are highly regulated by an intracellular signaling
pathway known as the unfolded protein response (UPR). The UPR provides a mechanism
by which cells can rapidly adapt to alterations in client protein-folding load in
the ER lumen by expanding the capacity for protein folding. In addition, a variety
of insults that disrupt protein folding in the ER lumen also activate the UPR. These
include changes in intralumenal calcium, altered glycosylation, nutrient deprivation,
pathogen infection, expression of folding-defective proteins, and changes in redox
status. Persistent protein misfolding initiates apoptotic cascades that are now known
to play fundamental roles in the pathogenesis of multiple human diseases including
diabetes, atherosclerosis and neurodegenerative diseases.