Endoplasmic reticulum and the unfolded protein response: dynamics and metabolic integration

Abstract

The endoplasmic reticulum (ER) is a dynamic intracellular organelle with multiple functions essential for cellular homeostasis, development, and stress responsiveness. In response to cellular stress, a well-established signaling cascade, the unfolded protein response (UPR), is activated. This intricate mechanism is an important means of re-establishing cellular homeostasis and alleviating the inciting stress. Now, emerging evidence has demonstrated that the UPR influences cellular metabolism through diverse mechanisms, including calcium and lipid transfer, raising the prospect of involvement of these processes in the pathogenesis of disease, including neurodegeneration, cancer, diabetes mellitus and cardiovascular disease. Here, we review the distinct functions of the ER and UPR from a metabolic point of view, highlighting their association with prevalent pathologies.

Fig 5.1. ER structure and general functions

Upper panel: The ER can be subdivided into three well-defined domains, the sheet-like ER, the tubular ER and the nuclear envelope. The first one is characterized as being rich in ribosomes, for which it received the name rough ER. Since the tubular ER contains fewer ribosomes, it is commonly called smooth ER. Both the sheet-like and tubular ER are highly dynamic and interconvert between each other constantly. Most studies suggest that the tubular ER has the ability to fuse, elongate and branch dynamically inside the cell. Lower panel: The ER fulfills diverse functions in the cell, like calcium homeostasis through the use of a series of channels, pumps and buffer proteins. It is essential for lipid and protein synthesis, as well as the quality control and degradation of proteins. Together with the Golgi apparatus, it takes part in the process of cell trafficking, which is important for the export of products from reticulum toward the outside of the cell. Finally, the ER also regulates the function of other organelles, such as mitochondria through dynamic interaction zones called MAM.

Fig 5.2. ER stress signaling

Upper panel: In resting conditions, the stress sensors IRE1 and PERK and ATF6 interact with Bip/GRP78. Accumulation of misfolded proteins in the ER lumen separates the chaperone from each sensor. IRE1α and PERK activation involves oligomerization and transphosphorylation of their cytosolic effector region. ATF6 activation, on the other hand, requires its transport to the Golgi, where it is sequentially cleaved by S1P and S2P. A recent model for IRE1α activation, involves an initial dissociation of BiP/GRP78 that drives sensor oligomerization, while subsequent binding to unfolded proteins leads to activation. Lower panel: The signaling engaged by the three sensors activates several transcription factors (XBP1, ATF4, p50ATF6, NF-κ B, CHOP) and protein kinases (JNK, AKT), leading to the establishment of a genetic program termed unfolded protein response. This adaptive response involves chaperone induction, activation of degradation pathways like the proteasome and autophagy, ER expansion and increased antioxidant defense. Also, the PERK pathway inhibits general mRNA translation, through eIF2α phosphorylation. If the cell does not reduce the mis-folded protein overload, apoptosis is triggered.

Fig 5.3. Proteins synthesized in the ER are subject to a quality control system

The lectins, calnexin and calreticulin retain glycosylated proteins in the ER through re/deglucosylation cycles until they reach their native conformation. Folded proteins are exported through vesicle trafficking, while terminally misfolded proteins are degraded through retrotranslocation and the ubiquitin–proteasome system or autophagy.

Fig 5.4. The ER modulates important metabolic pathways during ER stress

PERK induces global attenuation in protein anabolism, and also favors lipid synthesis, both effects via eIF2α phosphorylation. IRE1 cooperates with these responses and stimulates mitochondrial biogenesis through the regulation of master metabolic switches, such as PGC1α, mTOR, AMPK and FOXO1. ATF6, on the other hand, stimulates lipid utilization. Calcium released by IP3R increases mitochondrial activity during ER stress, in order to revert energy imbalance.

Fig 5.5. ER and pathologies

ER stress and alterations in cellular calcium characterize diverse pathologies such as type-2 diabetes mellitus, insulin resistance, and some cardiovascular and neurodegenerative diseases. These pathologies are also characterized by marked decrease in cellular metabolism, which is accompanied with protein misfolding and aggregation, and some characteristic hallmarks of UPR. However, the molecular mechanisms linking all these processes are not yet fully understood.