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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: closed (20 April 2023) | Viewed by 6908

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Dr. Gabriella Simbula

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Department of Biomedical Science, Oncology and Molecular Pathology Unit, University of Cagliari, 09124 Cagliari, Italy
Interests: signal transduction pathways involved in apoptosis and cell proliferation; endoplasmic reticulum stress; mitochondria; natural antioxidants; hepatocarcinoma
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Special Issue Information

Dear Colleagues,

The ability to respond to the perturbation of ER function (i.e., “ER stress”) is critical for cell survival, as chronic or unresolved ER stress can lead to cell death by apoptosis. In this context, a growing body of literature has shown a link between mitochondria and ER-stress in the pathogenesis of the apoptotic process. ER stress-dependent apoptosis may contribute to the development of several common diseases, including diabetes, neurodegenerative diseases, atherosclerosis, severe vision disorders, metabolic syndrome and kidney disease. On the other hand, several studies have shown that prolonged ER stress can also promote tumour cell apoptosis, suggesting that the triggering of ER stress activation may provide a novel approach for the synthesis of future chemotherapeutic drugs. Further exploration of the molecular pathways underlying ER-stress-induced apoptosis will greatly enhance our understanding about its role in common diseases and tumour development, as well as its possible modulation by novel pharmaceutical strategies.
This Special Issue will focus on the recent advances in our understanding of the role of ER stress and apoptosis in both the development of several common diseases and the selective elimination of cancer cells. We look forward to receiving your valuable submissions.

Possible topics include, but are not limited to:

Apoptosis;
Endoplasmic reticulum stress;
Unfolded protein response (UPR);
Mitochondrial dysfunction;
Biomarkers for ER stress;
Molecular mechanisms;
Degenerative diseases;
Metabolic diseases;
Tumours;
Novel pharmacological strategies.

Dr. Gabriella Simbula
Guest Editor

Manuscript Submission Information

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Keywords

apoptosis
endoplasmic reticulum stress
UPR
mitochondria dysfunction
molecular mechanisms
tumours
degenerative diseases
diabetes
metabolic diseases
novel pharmacological strategies

Published Papers (4 papers)

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Research

15 pages, 2090 KiB

Open AccessArticle

Tauroursodeoxycholic Acid Supplementation in In Vitro Culture of Indicine Bovine Embryos: Molecular and Cellular Effects on the In Vitro Cryotolerance

by Elisa Mariano Pioltine, Camila Bortoliero Costa, Fernanda Fagali Franchi, Priscila Helena dos Santos and Marcelo Fábio Gouveia Nogueira

Int. J. Mol. Sci. 2023, 24(18), 14060; https://doi.org/10.3390/ijms241814060 - 14 Sep 2023

Viewed by 1007

Abstract

During embryo development, the endoplasmic reticulum (ER) acts as an important site for protein biosynthesis; however, in vitro culture (IVC) can negatively affect ER homeostasis. Therefore, the aim of our study was to evaluate the effects of the supplementation of tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, in the IVC of bovine embryos. Two experiments were carried out: Exp. 1: an evaluation of blastocyst rate, hatching kinetics, and gene expression of hatched embryos after being treated with different concentrations of TUDCA (50, 200, or 1000 μM) in the IVC; Exp. 2: an evaluation of the re-expansion, hatching, and gene expression of hatched embryos previously treated with 200 µM of TUDCA at IVC and submitted to vitrification. There was no increase in the blastocyst and hatched blastocyst rates treated with TUDCA in the IVC. However, embryos submitted to vitrification after treatment with 200 µM of TUDCA underwent an increased hatching rate post-warming together with a down-regulation in the expression of ER stress-related genes and the accumulation of lipids. In conclusion, this work showed that the addition of TUDCA during in vitro culture can improve the cryotolerance of the bovine blastocyst through the putative modulation of ER and oxidative stress. Full article

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

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15 pages, 3648 KiB

Open AccessArticle

Identification of EGF Receptor and Thrombospondin-1 as Endogenous Targets of ER-Associated Degradation Enhancer EDEM1 in HeLa Cells

by Kohta Miura, Riko Katsuki, Shusei Yoshida, Ren Ohta and Taku Tamura

Int. J. Mol. Sci. 2023, 24(15), 12171; https://doi.org/10.3390/ijms241512171 - 29 Jul 2023

Cited by 1 | Viewed by 1097

Abstract

Secretory and membrane proteins are vital for cell activities, including intra- and intercellular communication. Therefore, protein quality control in the endoplasmic reticulum (ER) is an essential and crucial process for eukaryotic cells. Endoplasmic reticulum-associated degradation (ERAD) targets misfolded proteins during the protein maturation process in the ER and leads to their disposal. This process maintains the ER productive function and prevents misfolded protein stress (i.e., ER stress). The ERAD-stimulating factor ER degradation-enhancing α mannosidase-like 1 protein (EDEM1) acts on misfolded proteins to accelerate ERAD, thereby maintaining the productivity of the ER. However, the detail mechanism underlying the function of EDEM1 in ERAD is not completely understood due to a lack of established physiological substrate proteins. In this study, we attempted to identify substrate proteins for EDEM1 using siRNA. The matrix component thrombospondin-1 (TSP1) and epidermal growth factor receptor (EGFR) were identified as candidate targets of EDEM1. Their protein maturation status and cellular localization were markedly affected by knockdown of EDEM1. We also showed that EDEM1 physically associates with EGFR and enhances EGFR degradation via ERAD. Our data highlight the physiological role of EDEM1 in maintaining specific target proteins and provide a potential approach to the regulation of expression of clinically important proteins. Full article

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

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17 pages, 9344 KiB

Open AccessArticle

The Prohibitin-Binding Compound Fluorizoline Activates the Integrated Stress Response through the eIF2α Kinase HRI

by Ismael Sánchez-Vera, Sonia Núñez-Vázquez, José Saura-Esteller, Ana M. Cosialls, Judith Heib, Pau Nadal Rodríguez, Ouldouz Ghashghaei, Rodolfo Lavilla, Gabriel Pons, Joan Gil and Daniel Iglesias-Serret

Int. J. Mol. Sci. 2023, 24(9), 8064; https://doi.org/10.3390/ijms24098064 - 29 Apr 2023

Cited by 2 | Viewed by 1880

Abstract

Fluorizoline is a synthetic molecule that induces apoptosis, by selectively targeting prohibitins (PHBs), through induction of the BH3-only protein NOXA. This induction is transcriptionally regulated by the integrated stress response (ISR)-related transcription factors ATF3 and ATF4. Here, we evaluate the role of the four eIF2α kinases, to decipher which is responsible for the mechanism of ISR activation triggered by fluorizoline in HeLa and HAP1 cells. First, we demonstrated the involvement of the eIF2α kinases using ISR inhibitor (ISRIB) and by simultaneous downregulation of all four eIF2α kinases, as both approaches were able to increase cell resistance to fluorizoline-induced apoptosis. Furthermore, we confirmed that fluorizoline treatment results in endoplasmic reticulum (ER) stress, as evidenced by PERK activation. Despite PERK activation, this kinase was not directly involved in the ISR activation by fluorizoline. In this regard, we found that the eIF2α kinases are capable of compensating for each other’s loss of function. Importantly, we demonstrated that the mitochondrial-stress-related eIF2α kinase HRI mediates ISR activation after fluorizoline treatment. Full article

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

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15 pages, 3245 KiB

Open AccessArticle

Zearalenone Promotes LPS-Induced Oxidative Stress, Endoplasmic Reticulum Stress, and Accelerates Bovine Mammary Epithelial Cell Apoptosis

by Yurong Fu, Yongcheng Jin, Yue Tian, Hao Yu, Ruqi Wang, Huiyu Qi, Bo Feng and Jing Zhang

Int. J. Mol. Sci. 2022, 23(18), 10925; https://doi.org/10.3390/ijms231810925 - 18 Sep 2022

Cited by 14 | Viewed by 2231

Abstract

Both zearalenone (ZEA) and lipopolysaccharide (LPS) can induce oxidative stress, and even apoptosis in bovine mammary epithelial cells (MAC-T), but not much attention has been given to the synergistic effect of ZEA and LPS. In this study, we treated MAC-T cells with different concentrations of LPS (1, 10, 50, and 100 μg/mL) and ZEA (5, 15, and 30 μM) to induce cell damage. Previous results show that MAC-T cell viability decreases with increasing LPS concentration. Meanwhile, 1 µg/mL LPS and ZEA were selected for combined treatment in subsequent studies. It was found that co-treatment with ZEA and LPS increases the accumulation of reactive oxygen species (ROS) and malondialdehyde (MDA), decreases mitochondrial membrane potential (MMP), and superoxide dismutase (SOD), and reduces glutathione (GSH). ZEA and LPS are found to activate endoplasmic reticulum (ER) stress by increasing the expression of glucose-regulated protein 78 kDa (GRP78), activating transcription factor 6 (ATF6) and C/EBP homologous protein (CHOP). It increases cell apoptosis by suppressing the expression of the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2), indicated by up-regulation of Bcl2-associated X protein (Bax) and Cysteinyl aspartate-specific proteinases 3 (caspase-3) expression. The above results suggest that the synergistic effect of ZEA and LPS aggravate cytotoxicity. Full article

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

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