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Advances in Endoplasmic Reticulum Stress and Apoptosis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 20 February 2025 | Viewed by 7371

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Special Issue Editors

Dr. Orsolya Kapuy

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Guest Editor

Department of Molecular Biology, Semmelweis University, 1094 Budapest, Hungary
Interests: endoplasmic reticulum stress; autophagy; cellular survival; systems biology

Dr. Beáta Lizák

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Guest Editor

Department of Molecular Biology and Pathobiochemistry, Semmelweis University, 1094 Budapest, Hungary
Interests: endoplasmic reticulum stress; redox homeostasis of ER; ER membrane transporters

Special Issue Information

Dear Colleagues,

The endoplasmic reticulum (ER) acts as an essential integrator of external and internal stimuli in order to preserve cellular homeostasis. This process is tightly regulated by a complex network of signalling pathways called the unfolded protein response (UPR). The accumulation of incorrectly folded proteins or metabolic imbalance in ER lumen leads to ER stress, which primarily triggers the adaptive functions of UPR to avoid cell damage. If readjustment efforts fail, unresolved ER stress can lead to cell death mechanisms including apoptosis and other newly described cell killing processes. Autophagy was also claimed to be initiated by ER stress as a protective pathway from cell damage. The role of ER stress is becoming increasingly important in a wide range of human diseases; it is always appropriate to update its effects as thoroughly as possible.

The goal of this Special Issue is to showcase both the development and the current challenges/benefits of studying ER stress and the related signalling pathways. This Special Issue will include both review articles and original research papers to address the diversity of pathways in cell death initiated by ER imbalance and their integration in various diseases.

Dr. Orsolya Kapuy
Dr. Beáta Lizák
Guest Editors

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Keywords

ER stress
apoptosis initiated by ER stress
cellular survival
redox homeostasis of ER
autophagy initiated by ER stress
cell death pathways initiated by ER stress

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Published Papers (7 papers)

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Research

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20 pages, 3837 KiB

Open AccessArticle

NF-κB Transcription Factors: Their Distribution, Family Expansion, Structural Conservation, and Evolution in Animals

by Siphesihle Msweli, Suresh B. Pakala and Khajamohiddin Syed

Int. J. Mol. Sci. 2024, 25(18), 9793; https://doi.org/10.3390/ijms25189793 - 10 Sep 2024

Viewed by 409

Abstract

The Nuclear Factor Kappa B (NF-κB) transcription factor family consists of five members: RelA (p65), RelB, c-Rel, p50 (p105/NF-κB1), and p52 (p100/NF-κB2). This family is considered a master regulator of classical biochemical pathways such as inflammation, immunity, cell proliferation, and cell death. The proteins in this family have a conserved Rel homology domain (RHD) with the following subdomains: DNA binding domain (RHD-DBD) and dimerization domain (RHD-DD). Despite the importance of the NF-κB family in biology, there is a lack of information with respect to their distribution patterns, evolution, and structural conservation concerning domains and subdomains in animals. This study aims to address this critical gap regarding NF-κB proteins. A comprehensive analysis of NF-κB family proteins revealed their distinct distribution in animals, with differences in protein sizes, conserved domains, and subdomains (RHD-DBD and RHD-DD). For the first time, NF-κB proteins with multiple RHD-DBDs and RHD-DDs have been identified, and in some cases, this is due to subdomain duplication. The presence of RelA/p65 exclusively in vertebrates shows that innate immunity originated in fishes, followed by amphibians, reptiles, aves, and mammals. Phylogenetic analysis showed that NF-κB family proteins grouped according to animal groups, signifying structural conservation after speciation. The evolutionary analysis of RHDs suggests that NF-κB family members p50/p105 and c-Rel may have been the first to emerge in arthropod ancestors, followed by RelB, RelA, and p52/p100. Full article

(This article belongs to the Special Issue Advances in Endoplasmic Reticulum Stress and Apoptosis)

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26 pages, 9862 KiB

Open AccessArticle

TXNDC5 Plays a Crucial Role in Regulating Endoplasmic Reticulum Activity through Different ER Stress Signaling Pathways in Hepatic Cells

by Seyed Hesamoddin Bidooki, Cristina Barranquero, Javier Sánchez-Marco, Roberto Martínez-Beamonte, María J. Rodríguez-Yoldi, María A. Navarro, Susana C. M. Fernandes and Jesús Osada

Int. J. Mol. Sci. 2024, 25(13), 7128; https://doi.org/10.3390/ijms25137128 - 28 Jun 2024

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Abstract

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is influenced by a number of variables, including endoplasmic reticulum stress (ER). Thioredoxin domain-containing 5 (TXNDC5) is a member of the protein disulfide isomerase family and acts as an endoplasmic reticulum (ER) chaperone. Nevertheless, the function of TXNDC5 in hepatocytes under ER stress remains largely uncharacterized. In order to identify the role of TXNDC5 in hepatic wild-type (WT) and TXNDC5-deficient (KO) AML12 cell lines, tunicamycin, palmitic acid, and thapsigargin were employed as stressors. Cell viability, mRNA, protein levels, and mRNA splicing were then assayed. The protein expression results of prominent ER stress markers indicated that the ERN1 and EIF2AK3 proteins were downregulated, while the HSPA5 protein was upregulated. Furthermore, the ATF6 protein demonstrated no significant alterations in the absence of TXNDC5 at the protein level. The knockout of TXNDC5 has been demonstrated to increase cellular ROS production and its activity is required to maintain normal mitochondrial function during tunicamycin-induced ER stress. Tunicamycin has been observed to disrupt the protein levels of HSPA5, ERN1, and EIF2AK3 in TXNDC5-deficient cells. However, palmitic acid has been observed to disrupt the protein levels of ATF6, HSPA5, and EIF2AK3. In conclusion, TXNDC5 can selectively activate distinct ER stress pathways via HSPA5, contingent on the origin of ER stress. Conversely, the absence of TXNDC5 can disrupt the EIF2AK3 cascade. Full article

(This article belongs to the Special Issue Advances in Endoplasmic Reticulum Stress and Apoptosis)

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20 pages, 10263 KiB

Open AccessArticle

Subcellular Localization of Thioredoxin/Thioredoxin Reductase System—A Missing Link in Endoplasmic Reticulum Redox Balance

by Krisztina Veszelyi, Ibolya Czegle, Viola Varga, Csilla Emese Németh, Balázs Besztercei and Éva Margittai

Int. J. Mol. Sci. 2024, 25(12), 6647; https://doi.org/10.3390/ijms25126647 - 17 Jun 2024

Viewed by 729

Abstract

The lumen of the endoplasmic reticulum (ER) is usually considered an oxidative environment; however, oxidized thiol-disulfides and reduced pyridine nucleotides occur there parallelly, indicating that the ER lumen lacks components which connect the two systems. Here, we investigated the luminal presence of the thioredoxin (Trx)/thioredoxin reductase (TrxR) proteins, capable of linking the protein thiol and pyridine nucleotide pools in different compartments. It was shown that specific activity of TrxR in the ER is undetectable, whereas higher activities were measured in the cytoplasm and mitochondria. None of the Trx/TrxR isoforms were expressed in the ER by Western blot analysis. Co-localization studies of various isoforms of Trx and TrxR with ER marker Grp94 by immunofluorescent analysis further confirmed their absence from the lumen. The probability of luminal localization of each isoform was also predicted to be very low by several in silico analysis tools. ER-targeted transient transfection of HeLa cells with Trx1 and TrxR1 significantly decreased cell viability and induced apoptotic cell death. In conclusion, the absence of this electron transfer chain may explain the uncoupling of the redox systems in the ER lumen, allowing parallel presence of a reduced pyridine nucleotide and a probably oxidized protein pool necessary for cellular viability. Full article

(This article belongs to the Special Issue Advances in Endoplasmic Reticulum Stress and Apoptosis)

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18 pages, 2728 KiB

Open AccessArticle

D-Allulose Reduces Hypertrophy and Endoplasmic Reticulum Stress Induced by Palmitic Acid in Murine 3T3-L1 Adipocytes

by Maria Sofia Molonia, Federica Lina Salamone, Antonio Speciale, Antonella Saija and Francesco Cimino

Int. J. Mol. Sci. 2024, 25(7), 4059; https://doi.org/10.3390/ijms25074059 - 5 Apr 2024

Cited by 1 | Viewed by 1211

Abstract

Natural rare sugars are an alternative category of sweeteners with positive physiologic and metabolic effects both in in vitro and animal models. D-allulose is a D-fructose epimer that combines 70% sucrose sweetness with the advantage of an extremely low energy content. However, there are no data about the effect of D-allulose against adipose dysfunction; thus, it remains to be confirmed whether D-allulose is useful in the prevention and in treatment of adipose tissue alterations. With this aim, we evaluated D-allulose’s preventive effects on lipid accumulation in 3T3-L1 murine adipocytes exposed to palmitic acid (PA), a trigger for hypertrophic adipocytes. D-allulose in place of glucose prevented adipocyte hypertrophy and the activation of adipogenic markers C/EBP-β and PPARγ induced by high PA concentrations. Additionally, D-allulose pretreatment inhibited the NF-κB pathway and endoplasmic reticulum stress caused by PA, through activation of the Nrf2 pathway. Interestingly, these effects were also observed as D-allulose post PA treatment. Although our data need to be confirmed through in vivo models, our findings suggest that incorporating D-allulose as a glucose substitute in the diet might have a protective role in adipocyte function and support a unique mechanism of action in this sugar as a preventive or therapeutic compound against PA lipotoxicity through the modulation of pathways connected to lipid transport and metabolism. Full article

(This article belongs to the Special Issue Advances in Endoplasmic Reticulum Stress and Apoptosis)

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20 pages, 2290 KiB

Open AccessArticle

The Dual Role of Sulforaphane-Induced Cellular Stress—A Systems Biological Study

by Marianna Holczer, Boglárka Besze, Annamária Lehel and Orsolya Kapuy

Int. J. Mol. Sci. 2024, 25(2), 1220; https://doi.org/10.3390/ijms25021220 - 19 Jan 2024

Cited by 3 | Viewed by 1007

Abstract

The endoplasmic reticulum (ER) plays a crucial role in cellular homeostasis. When ER stress is generated, an autophagic self-digestive process is activated to promote cell survival; however, cell death is induced in the case of excessive levels of ER stress. The aim of the present study was to investigate the effect of a natural compound called sulforaphane (SFN) upon ER stress. Our goal was to investigate how SFN-dependent autophagy activation affects different stages of ER stress induction. We approached our scientific analysis from a systems biological perspective using both theoretical and molecular biological techniques. We found that SFN induced the various cell-death mechanisms in a concentration- and time-dependent manner. The short SFN treatment at low concentrations promoted autophagy, whereas the longer treatment at higher concentrations activated cell death. We proved that SFN activated autophagy in a mTORC1-dependent manner and that the presence of ULK1 was required for its function. A low concentration of SFN pre- or co-treatment combined with short and long ER stress was able to promote cell survival via autophagy induction in each treatment, suggesting the potential medical importance of SFN in ER stress-related diseases. Full article

(This article belongs to the Special Issue Advances in Endoplasmic Reticulum Stress and Apoptosis)

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17 pages, 5031 KiB

Open AccessArticle

Homer1 Protects against Retinal Ganglion Cell Pyroptosis by Inhibiting Endoplasmic Reticulum Stress-Associated TXNIP/NLRP3 Inflammasome Activation after Middle Cerebral Artery Occlusion-Induced Retinal Ischemia

by Weihao Lv, Xiuquan Wu, Yanan Dou, Yiwen Yan, Leiying Chen, Zhou Fei and Fei Fei

Int. J. Mol. Sci. 2023, 24(23), 16811; https://doi.org/10.3390/ijms242316811 - 27 Nov 2023

Cited by 5 | Viewed by 1217

Abstract

Retinal ischemia, after cerebral ischemia, is an easily overlooked pathophysiological problem in which inflammation is considered to play an important role. Pyroptosis is a kind of cell death pattern accompanied by inflammation. Homer scaffold protein 1 (Homer1) has anti-inflammation properties and protects against ischemic injury. However, little is known about pyroptosis following middle cerebral artery occlusion (MCAO)-induced retinal ischemia and the regulatory mechanisms involved by Homer1 for the development of pyroptosis. In the present study, retinal ischemic injury was induced in mice by permanent MCAO in vivo, and retinal ganglion cells (RGCs) were subjected to Oxygen and Glucose Deprivation (OGD) to establish an in vitro model. It was shown that TXNIP/NLRP3-mediated pyroptosis was located predominantly in RGCs, which gradually increased after retinal ischemia and peaked at 24 h after retinal ischemia. Interestingly, the RGCs pyroptosis occurred not only in the cell body but also in the axon. Notably, the occurrence of pyroptosis coincided with the change of Homer1 expression in the retina after retinal ischemia and Homer1 also co-localized with RGCs. It was demonstrated that overexpression of Homer1 not only alleviated RGCs pyroptosis and inhibited the release of pro-inflammatory factors but also led to the increase in phosphorylation of AMPK, inhibition of ER stress, and preservation of visual function after retinal ischemia. In conclusion, it was suggested that Homer1 may protect against MCAO-induced retinal ischemia and RGCs pyroptosis by inhibiting endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation after MCAO-induced retinal ischemia. Full article

(This article belongs to the Special Issue Advances in Endoplasmic Reticulum Stress and Apoptosis)

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Review

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17 pages, 1526 KiB

Open AccessReview

Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress

by Orsolya Kapuy

Int. J. Mol. Sci. 2024, 25(8), 4368; https://doi.org/10.3390/ijms25084368 - 15 Apr 2024

Cited by 4 | Viewed by 1148

Abstract

Dynamic regulation of the cellular proteome is mainly controlled in the endoplasmic reticulum (ER). Accumulation of misfolded proteins due to ER stress leads to the activation of unfolded protein response (UPR). The primary role of UPR is to reduce the bulk of damages and try to drive back the system to the former or a new homeostatic state by autophagy, while an excessive level of stress results in apoptosis. It has already been proven that the proper order and characteristic features of both surviving and self-killing mechanisms are controlled by negative and positive feedback loops, respectively. The new results suggest that these feedback loops are found not only within but also between branches of the UPR, fine-tuning the response to ER stress. In this review, we summarize the recent knowledge of the dynamical characteristic of endoplasmic reticulum stress response mechanism by using both theoretical and molecular biological techniques. In addition, this review pays special attention to describing the mechanism of action of the dynamical features of the feedback loops controlling cellular life-and-death decision upon ER stress. Since ER stress appears in diseases that are common worldwide, a more detailed understanding of the behaviour of the stress response is of medical importance. Full article

(This article belongs to the Special Issue Advances in Endoplasmic Reticulum Stress and Apoptosis)

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