The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling

Abstract

The endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells. Its main functions include protein synthesis, proper protein folding, protein modification, and the transportation of synthesized proteins. Any perturbations in ER function, such as increased demand for protein folding or the accumulation of unfolded or misfolded proteins in the ER lumen, lead to a stress response called the unfolded protein response (UPR). The primary aim of the UPR is to restore cellular homeostasis; however, it triggers apoptotic signaling during prolonged stress. The core mechanisms of the ER stress response, the failure to respond to cellular stress, and the final fate of the cell are not yet clear. Here, we discuss cellular fate during ER stress, cross talk between the ER and mitochondria and its significance, and conditions that can trigger ER stress response failure. We also describe how the redox environment affects the ER stress response, and vice versa, and the aftermath of the ER stress response, integrating a discussion on redox imbalance-induced ER stress response failure progressing to cell death and dynamic pathophysiological changes.

Fig. 1. General unfolded protein response pathway during ER stress.

GRP78/BiP, an ER chaperone, is closely associated with three sensors of the UPR, IRE1, PERK, and ATF6, inhibiting them under normal physiological conditions. Upon ER stress or misfolded protein accumulation, GRP78 dissociates from all these UPR transducers and permits stress sensors to activate downstream signaling. A different signal transduction system activates each pathway. The most conserved signal transducer, IRE1 (which contains a serine/threonine kinase and an RNase domain on its cytosolic side), undergoes homodimerization and autophosphorylation, and its activation mediates the activation of its RNase domain to produce spliced XBP1 mRNA, which is the active isoform of XBP1 that is translocated to the nucleus to increase UPR target genes, including chaperones and ERAD. The RNase domain of IRE1 also regulates the RIDD (regulated IRE1-dependent decay) pathway, where IRE1 degrades ER membrane-localized mRNAs through its RNase activity, resulting in a reduction in the amount of protein imported into the ER lumen. Similarly, during ER stress, the cytosolic domain of IRE1 interacts with TRAF2 and activates the downstream kinase ASK1, enhancing the activated JNK pathway and triggering apoptosis. Similarly, activation of PERK increases the phosphorylation of the alpha subunit of the translation protein eIF2, which attenuates protein translation to reduce ER protein overload, while paradoxically upregulating ATF4 mRNA, which targets the activation of proapoptotic CHOP and other UPR target genes. Upon sensing ER stress, a third UPR transducer, ATF6 alpha, is translocated to the Golgi apparatus, where it undergoes cleavage by site-1 and site-2 proteases. The cleaved fragments are then translocated to the nucleus and activate the transcriptional target genes of ATF6, including chaperones and XBP1. Adaptive response failure may not resolve ER stress and may upregulate UPR signaling to induce apoptosis.

Fig. 2. Cross talk between components of ER stress and the redox signaling pathway.

During various pathological conditions, unfolded or misfolded proteins are increased in the ER. During oxidative protein folding in the ER, ROS are generated during electron transfer between PDI and ERO1α. ROS associated with UPR signaling can activate an antioxidant response, such as Nrf2 or can increase ROS generation by activating ERO1 or NOX. Furthermore, ROS are increased in the ER through the association of PDI with ROS, generating Nox4. Although the major site of calcium is in the ER, under stress conditions, calcium may flow to the mitochondrial outer membrane through calcium release channels, such as IP3R or RyR. Increased calcium overload in mitochondria subsequently increases ROS generation. The increased calcium load and ROS in mitochondria may lead to opening of the mitochondrial permeability transition pore, which may cause the release of proapoptotic factors. High oxidative stress during this condition is critical for inducing mitochondrial dysfunction and vice versa. Overall, we suggest that the ER stress response can induce ER or mitochondrial dysfunction, which may increase oxidative stress by dysregulating disulfide bond formation, impairing oxidative protein folding, or the inducing certain UPR genes (e.g., CHOP) where oxidative stress is reversible, which may depend on redox homeostasis (see the text for more details). ER endoplasmic reticulum, ROS reactive oxygen species, PDI protein disulfide isomerase, ERO1α endoplasmic reticulum oxidoreduction 1α, NOX NADPH oxidase, IP3R inositol 1,4,5-trisphosphate receptors, RyR ryanodine receptors.

Fig. 3. ER stress response failure and cellular fate.

During acute or short-term ER stress, the cell follows its natural adaptive pathway (as explained in Fig. 1) to maintain cellular homeostasis. However, during prolonged ER stress or under certain conditions, such as aging or metabolic diseases (e.g., obesity or diabetes), the activated UPR sensors may not activate downstream signaling (here, we focus on IRE1 signaling). For example, failure of XBP1s to translocate to the nucleus to activate its target genes leads to decreased activation of XBP1s target genes, such as chaperones or ERAD. This diminished effect is called ER stress response failure, which may trigger apoptotic signaling rather than adaptive responses. Evidence of ER response failure in metabolic diseases suggests that the impaired interaction of XBP1s with the insulin receptor or the regulatory subunits of PI3K p85α and p85β blocks XBP1s translocation to the nucleus. Similarly, excessive reactive oxygen species and/or reactive nitrogen species-induced nitro-oxidative stress production induces sulfonation (SO3H) of IRE1 or SNO of IRE1α, which can decrease IRE1α ribonuclease activity, thereby inhibiting the production of XBP1s^,,. This impaired signaling may disrupt the ER chaperones, ERAD, or their functions, which may negatively affect cell survival and trigger apoptosis, leading to the subsequent disease progression.