The Endoplasmic Reticulum: Folding, Calcium Homeostasis, Signaling, and Redox Control

Abstract

The endoplasmic reticulum (ER) plays a major role in regulating synthesis, folding, and orderly transport of proteins. It is also essentially involved in various cellular signaling processes, primarily by its function as a dynamic Ca(2+) store. Compared to the cytosol, oxidizing conditions are found in the ER that allow oxidation of cysteine residues in nascent polypeptide chains to form intramolecular disulfide bonds. However, compounds and enzymes such as PDI that catalyze disulfide bonds become reduced and have to be reoxidized for further catalytic cycles. A number of enzymes, among them products of the ERO1 gene, appear to provide oxidizing equivalents, and oxygen appears to be the final oxidant in aerobic living organisms. Thus, protein oxidation in the ER is connected with generation of reactive oxygen species (ROS). Changes in the redox state and the presence of ROS also affect the Ca(2+) homeostasis by modulating the functionality of ER-based channels and buffering chaperones. In addition, a close relationship exists between oxidative stress and ER stress, which both may activate signaling events leading to a rebalance of folding capacity and folding demand or to cell death. Thus, redox homeostasis appears to be a prerequisite for proper functioning of the ER.

The roles of oxidative stress, endoplasmic reticulum stress, and autophagy in aldosterone/mineralocorticoid receptor-induced podocyte injury

“…48 Consistent with these previous reports, we confirmed that inhibition of ROS with NAC, a widely used antioxidant, significantly attenuated the cytotoxicity of aldosterone. Oxidative stress is a known inducer of ER stress 49 and autophagy. 50 As expected, the current study revealed the enhanced effect of aldosterone-induced podocyte ER stress and autophagy was inhibited by antioxidants.…”

STEAP1 Is Associated with the Invasive and Oxidative Stress Phenotype of Ewing Tumors

“…ROS participate in oncogenic signaling and elevated ROS levels are a salient feature of aggressive cancers (17,18). Disturbances in the delicate ROS balance can lead to protein misfolding, accumulation of dysfunctional proteins, and activation of cellular stress responses (36). In accordance, STEAP1 silencing provokes transcriptional and posttranscriptional adaptations of oxidative stress responses comprising the redox, chaperone, endopeptidase, and UPS.…”

“…Among these proteins are several redox enzymes such as peroxiredoxins and superoxide dismutases, which are dysregulated in a large cohort of cancers (15,34). Moreover, endosomal redox stress response proteins (35,36) were identified including T-complex chaperones, heat shock proteins, protein-disulfide isomerases as well as co-chaperones. Furthermore, we identified mediators of posttranscriptional mRNA processing such as heterogeneous nuclear ribonucleoproteins, THO complex proteins, and eukaryotic translation initiation factors (Supplementary Table S4).…”

Endoplasmic reticulum calcium release potentiates the ER stress and cell death caused by an oxidative stress in MCF-7 cells

“…Another possibility is that reactive oxygen species (ROS) may cause ER stress through generation and accumulation of oxidized proteins [11,17]. The ER appears to be particularly sensitive to such modifications [18][19][20][21], as its molecular environment has a high oxidizing redox potential, specialized in protein folding and disulfide bond formation [18,22,23]. Finally, ROS could directly damage proteins of the ER folding machinery, such as ER chaperones, and induce an accumulation of misfolded proteins and consequent UPR activation.…”