scholarly journals Potential Roles of Endoplasmic Reticulum Stress and Cellular Proteins Implicated in Diabesity

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Sagir Mustapha ◽  
Mustapha Mohammed ◽  
Ahmad Khusairi Azemi ◽  
Ismaeel Yunusa ◽  
Aishatu Shehu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Unfolded Protein ◽  
Metabolic Functions ◽  
Chronic Hyperglycemia ◽  
Obesity And Diabetes ◽  
Activating Transcription Factor ◽  
Protein Response

The role of the endoplasmic reticulum (ER) has evolved from protein synthesis, processing, and other secretory pathways to forming a foundation for lipid biosynthesis and other metabolic functions. Maintaining ER homeostasis is essential for normal cellular function and survival. An imbalance in the ER implied stressful conditions such as metabolic distress, which activates a protective process called unfolded protein response (UPR). This response is activated through some canonical branches of ER stress, i.e., the protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6). Therefore, chronic hyperglycemia, hyperinsulinemia, increased proinflammatory cytokines, and free fatty acids (FFAs) found in diabesity (a pathophysiological link between obesity and diabetes) could lead to ER stress. However, limited data exist regarding ER stress and its association with diabesity, particularly the implicated proteins and molecular mechanisms. Thus, this review highlights the role of ER stress in relation to some proteins involved in diabesity pathogenesis and provides insight into possible pathways that could serve as novel targets for therapeutic intervention.

scholarly journals Endoplasmic Reticulum-Associated Biomarkers for Molecular Phenotyping of Rare Kidney Disease

2021 ◽  
Vol 22 (4) ◽  
pp. 2161
Author(s):  
Chuang Li ◽  
Ying Maggie Chen
Keyword(s):  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Er Stress ◽  
Protein Kinase R ◽  
Post Translational Modifications ◽  
Unfolded Protein ◽  
Novel Biomarkers ◽  
Activating Transcription Factor ◽  
Protein Response

The endoplasmic reticulum (ER) is the central site for folding, post-translational modifications, and transport of secretory and membrane proteins. An imbalance between the load of misfolded proteins and the folding capacity of the ER causes ER stress and an unfolded protein response. Emerging evidence has shown that ER stress or the derangement of ER proteostasis contributes to the development and progression of a variety of glomerular and tubular diseases. This review gives a comprehensive summary of studies that have elucidated the role of the three ER stress signaling pathways, including inositol-requiring enzyme 1 (IRE1), protein kinase R-like ER kinase (PERK), and activating transcription factor 6 (ATF6) signaling in the pathogenesis of kidney disease. In addition, we highlight the recent discovery of ER-associated biomarkers, including MANF, ERdj3, ERdj4, CRELD2, PDIA3, and angiogenin. The implementation of these novel biomarkers may accelerate early diagnosis and therapeutic intervention in rare kidney disease.

scholarly journals Nox4 Mediates RANKL-induced ER-Phagy and Osteoclastogenesis via Activating ROS/PERK/eIF-2α/ATF4 Pathway

2020 ◽  
Author(s):  
Jing Sun ◽  
wugui chen ◽  
Songtao Li ◽  
Sizhen Yang ◽  
Ying Zhang ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Bone Resorption ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Nuclear Factor Κb ◽  
Protein Levels ◽  
Unfolded Protein ◽  
Regulatory Effects ◽  
Protein Response

Abstract Background: Receptor activator of nuclear factor-κB ligand (RANKL) has been found to induce osteoclastogenesis and bone resorption. However, the underlying molecular mechanisms remain unclear. Methods: Osteoclastogenesis was evaluated by number of TRAP-positive multinuclear (≥3) osteoclasts, bone resorption pits and expression levels of related genes. Autophagy activity were evaluated by LC3-II/LC3-I ratio, number of autophagic vacuoles and adenovirus-mRFP-GFP-tagged LC3 reporting system; Inhibitor chloroquine (CQ) was used to verified the role of autophagy in RANKL-induced osteoclastogenesis; Via downregulating Nox4 with inhibitor (DPI) and retrovirus-conveyed shRNA, we further explored the importance of Nox4 in RANKL-induced autophagy and osteoclastogenesis, as well as the regulatory effects of Nox4 on nonmitochondrial reactive oxygen species (ROS) and PERK/eIF-2α/ATF4 pathway. Intracellular ROS scavenger (NAC), mitochondrial-targeted antioxidant (MitoTEMPO) and inhibitor of PERK (GSK2606414) were also employed to investigate the role of ROS and PERK/eIF-2α/ATF4 pathway in RANKL-induced autophagy and osteoclastogenesis. Results: RANKL markedly increased autophagy, while CQ treatment caused reduction of RANKL-induced autophagy and osteoclastogenesis. Consistent with the increased autophagy, the protein levels of Nox4 were significantly increased, and Nox4 was selectively localized within the endoplasmic reticulum (ER) after RANKL stimulation. DPI and shRNA efficiently decreased the protein level and (or) activity of Nox4 in the ER and inhibited RANKL-induced autophagy and osteoclastogenesis. Mechanistically, we found that Nox4 regulates RANKL-induced autophagy activation and osteoclastogenesis by stimulating the production of nonmitochondrial ROS. Additionally, Nox4-derived nonmitochondrial ROS dramatically activate PERK/eIF-2α/ATF4, which is a critical unfolded protein response (UPR)-related signaling pathway during ER stress. Blocking the activation of the PERK/eIF-2α/ATF4 signaling pathway either by Nox4 shRNA, ROS antioxidant or PERK inhibitor (GSK2606414) treatment significantly inhibited endoplasmic reticulum autophagy (ER-phagy) during RANKL-induced osteoclastogenesis. Conclusions: Our findings provide new insights into the processes of RANKL-induced osteoclastogenesis and will help the development of new therapeutic strategies for osteoclastogenesis-related diseases.

scholarly journals The Role of Endoplasmic Reticulum Stress in Cardiovascular Disease and Exercise

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Junyoung Hong ◽  
Kwangchan Kim ◽  
Jong-Hee Kim ◽  
Yoonjung Park
Keyword(s):  
Cardiovascular Disease ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Signaling Pathways ◽  
Protein Misfolding ◽  
Unfolded Protein ◽  
Activating Transcription Factor ◽  
Apoptosis And Inflammation ◽  
The Unfolded Protein Response

Endoplasmic reticulum (ER) stress, which is highly associated with cardiovascular disease, is triggered by a disturbance in ER function because of protein misfolding or an increase in protein secretion. Prolonged disruption of ER causes ER stress and activation of the unfolded protein response (UPR) and leads to various diseases. Eukaryotic cells respond to ER stress via three major sensors that are bound to the ER membrane: activating transcription factor 6 (ATF6), inositol-requiring protein 1α (IRE1α), and protein kinase RNA-like ER kinase (PERK). Chronic activation of ER stress causes damage in endothelial cells (EC) via apoptosis, inflammation, and oxidative stress signaling pathways. The alleviation of ER stress has recently been accepted as a potential therapeutic target to treat cardiovascular diseases such as heart failure, hypertension, and atherosclerosis. Exercise training is an effective nonpharmacological approach for preventing and alleviating cardiovascular disease. We here review the recent viewing of ER stress-mediated apoptosis and inflammation signaling pathways in cardiovascular disease and the role of exercise in ER stress-associated diseases.

scholarly journals A Mouse Model Suggests Two Mechanisms for Thyroid Alterations in Infantile Cystinosis: Decreased Thyroglobulin Synthesis Due to Endoplasmic Reticulum Stress/Unfolded Protein Response and Impaired Lysosomal Processing

Endocrinology ◽  
2015 ◽  
Vol 156 (6) ◽  
pp. 2349-2364 ◽  
Author(s):  
H. P. Gaide Chevronnay ◽  
V. Janssens ◽  
P. Van Der Smissen ◽  
X. H. Liao ◽  
Y. Abid ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Molecular Mechanisms ◽  
Primary Hypothyroidism ◽  
Overt Hypothyroidism ◽  
Nephropathic Cystinosis ◽  
Unfolded Protein ◽  
Activating Transcription Factor 4 ◽  
Protein Response

Abstract Thyroid hormones are released from thyroglobulin (Tg) in lysosomes, which are impaired in infantile/nephropathic cystinosis. Cystinosis is a lysosomal cystine storage disease due to defective cystine exporter, cystinosin. Cystinotic children develop subclinical and then overt hypothyroidism. Why hypothyroidism is the most frequent and earliest endocrine complication of cystinosis is unknown. We here defined early alterations in Ctns−/− mice thyroid and identified subcellular and molecular mechanisms. At 9 months, T4 and T3 plasma levels were normal and TSH was moderately increased (∼4-fold). By histology, hyperplasia and hypertrophy of most follicles preceded colloid exhaustion. Increased immunolabeling for thyrocyte proliferation and apoptotic shedding indicated accelerated cell turnover. Electron microscopy revealed endoplasmic reticulum (ER) dilation, apical lamellipodia indicating macropinocytic colloid uptake, and lysosomal cystine crystals. Tg accumulation in dilated ER contrasted with mRNA down-regulation. Increased expression of ER chaperones, glucose-regulated protein of 78 kDa and protein disulfide isomerase, associated with alternative X-box binding protein-1 splicing, revealed unfolded protein response (UPR) activation by ER stress. Decreased Tg mRNA and ER stress suggested reduced Tg synthesis. Coordinated increase of UPR markers, activating transcription factor-4 and C/EBP homologous protein, linked ER stress to apoptosis. Hormonogenic cathepsins were not altered, but lysosome-associated membrane protein-1 immunolabeling disclosed enlarged vesicles containing iodo-Tg and impaired lysosomal fusion. Isopycnic fractionation showed iodo-Tg accumulation in denser lysosomes, suggesting defective lysosomal processing and hormone release. In conclusion, Ctns−/− mice showed the following alterations: 1) compensated primary hypothyroidism and accelerated thyrocyte turnover; 2) impaired Tg production linked to ER stress/UPR response; and 3) altered endolysosomal trafficking and iodo-Tg processing. The Ctns−/− thyroid is useful to study disease progression and evaluate novel therapies.

scholarly journals Distinct roles of activating transcription factor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) in transcription during the mammalian unfolded protein response

2002 ◽  
Vol 366 (2) ◽  
pp. 585-594 ◽  
Author(s):  
Tetsuya OKADA ◽  
Hiderou YOSHIDA ◽  
Rieko AKAZAWA ◽  
Manabu NEGISHI ◽  
Kazutoshi MORI
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Protein Kinase ◽  
Er Stress ◽  
Double Stranded Rna ◽  
Unfolded Protein ◽  
Genes Encoding ◽  
Membrane Bound ◽  
Activating Transcription Factor ◽  
Protein Response

In response to accumulation of unfolded proteins in the endoplasmic reticulum (ER), a homoeostatic response, termed the unfolded protein response (UPR), is activated in all eukaryotic cells. The UPR involves only transcriptional regulation in yeast, and approx. 6% of all yeast genes, encoding not only proteins to augment the folding capacity in the ER, but also proteins working at various stages of secretion, are induced by ER stress [Travers, Patil, Wodicka, Lockhart, Weissman and Walter (2000) Cell (Cambridge, Mass.) 101, 249–258]. In the present study, we conducted microarray analysis of HeLa cells, although our analysis covered only a small fraction of the human genome. A great majority of human ER stress-inducible genes (approx. 1% of 1800 genes examined) were classified into two groups. One group consisted of genes encoding ER-resident molecular chaperones and folding enzymes, and these genes were directly regulated by the ER-membrane-bound transcription factor activating transcription factor (ATF) 6. The ER-membrane-bound protein kinase double-stranded RNA-activated protein kinase-like ER kinase (PERK)-mediated signalling pathway appeared to be responsible for induction of the remaining genes, which are not involved in secretion, but may be important after cellular recovery from ER stress. In higher eukaryotes, the PERK-mediated translational-attenuation system is known to operate in concert with the transcriptional-induction system. Thus we propose that mammalian cells have evolved a strategy to cope with ER stress different from that of yeast cells.

scholarly journals Exploring the Role of Endoplasmic Reticulum Stress in Hepatocellular Carcinoma through the Mining of the Human Protein Atlas

Biology ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 640
Author(s):  
Nataša Pavlović ◽  
Femke Heindryckx
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Predictive Biomarkers ◽  
Human Protein ◽  
Disease Stage ◽  
Unfolded Protein ◽  
Human Protein Atlas ◽  
Associated Proteins ◽  
Protein Response

Endoplasmic reticulum (ER) stress and actors of unfolded protein response (UPR) have emerged as key hallmarks of hepatocarcinogenesis. Numerous reports have shown that the main actors in the UPR pathways are upregulated in HCC and contribute to the different facets of tumor initiation and disease progression. Furthermore, ER-stress inducers and inhibitors have shown success in preclinical HCC models. Despite the mounting evidence of the UPR’s involvement in HCC pathogenesis, it remains unclear how ER-stress components can be used safely and effectively as therapeutic targets or predictive biomarkers for HCC patients. In an effort to add a clinical context to these findings and explore the translational potential of ER-stress in HCC, we performed a systematic overview of UPR-associated proteins as predictive biomarkers in HCC by mining the Human Protein Atlas database. Aside from evaluating the prognostic value of these markers in HCC, we discussed their expression in relation to patient age, sex, ethnicity, disease stage, and tissue localization. We thereby identified 44 UPR-associated proteins as unfavorable prognostic markers in HCC. The expression of these markers was found to be higher in tumors compared to the stroma of the hepatic HCC patient tissues.

scholarly journals Salicylic acid-independent role of NPR1 is required for protection from proteotoxic stress in the plant endoplasmic reticulum

2018 ◽  
Vol 115 (22) ◽  
pp. E5203-E5212 ◽  
Author(s):  
Ya-Shiuan Lai ◽  
Luciana Renna ◽  
John Yarema ◽  
Cristina Ruberti ◽  
Sheng Yang He ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Salicylic Acid ◽  
Er Stress ◽  
Stress Responses ◽  
Unfolded Protein ◽  
Redox Activation ◽  
Genetic Level ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is an ancient signaling pathway designed to protect cells from the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER). Because misregulation of the UPR is potentially lethal, a stringent surveillance signaling system must be in place to modulate the UPR. The major signaling arms of the plant UPR have been discovered and rely on the transcriptional activity of the transcription factors bZIP60 and bZIP28 and on the kinase and ribonuclease activity of IRE1, which splices mRNA to activate bZIP60. Both bZIP28 and bZIP60 modulate UPR gene expression to overcome ER stress. In this study, we demonstrate at a genetic level that the transcriptional role of bZIP28 and bZIP60 in ER-stress responses is antagonized by nonexpressor of PR1 genes 1 (NPR1), a critical redox-regulated master regulator of salicylic acid (SA)-dependent responses to pathogens, independently of its role in SA defense. We also establish that the function of NPR1 in the UPR is concomitant with ER stress-induced reduction of the cytosol and translocation of NPR1 to the nucleus where it interacts with bZIP28 and bZIP60. Our results support a cellular role for NPR1 as well as a model for plant UPR regulation whereby SA-independent ER stress-induced redox activation of NPR1 suppresses the transcriptional role of bZIP28 and bZIP60 in the UPR.

Endoplasmic Reticulum Stress Signaling Pathways: Activation and Diseases

2019 ◽  
Vol 20 (9) ◽  
pp. 935-943 ◽  
Author(s):  
Zhi Zheng ◽  
Yuxi Shang ◽  
Jiahui Tao ◽  
Jun Zhang ◽  
Bingdong Sha
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Misfolded Proteins ◽  
Endogenous Factors ◽  
Unfolded Protein ◽  
Dependent Protein ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Sensor Molecules

Secretory and membrane proteins are folded in the endoplasmic reticulum (ER) prior to their exit. When ER function is disturbed by exogenous and endogenous factors, such as heat shock, ultraviolet radiation, hypoxia, or hypoglycemia, the misfolded proteins may accumulate, promoting ER stress. To rescue this unfavorable situation, the unfolded protein response is activated to reduce misfolded proteins within the ER. Upon ER stress, the ER transmembrane sensor molecules inositol-requiring enzyme 1 (IRE1), RNA-dependent protein kinase (PKR)-like ER kinase (PERK), and activating transcription factor 6, are activated. Here, we discuss the mechanisms of PERK and IRE1 activation and describe two working models for ER stress initiation: the BiP-dependent model and the ligand-driven model. ER stress activation has been linked to multiple diseases, including cancers, Alzheimer’s disease, and diabetes. Thus, the regulation of ER stress may provide potential therapeutic targets for these diseases.

Endoplasmic reticulum stress signaling: the microRNA connection

2013 ◽  
Vol 304 (12) ◽  
pp. C1117-C1126 ◽  
Author(s):  
Marion Maurel ◽  
Eric Chevet
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Small Noncoding Rnas ◽  
Unfolded Protein ◽  
Transcriptional Reprogramming ◽  
Stress Sensors ◽  
Activating Transcription Factor ◽  
Stress Dependent ◽  
Protein Response ◽  
Er Homeostasis

The endoplasmic reticulum (ER)-induced unfolded protein response (ERUPR) is an adaptive mechanism that is activated upon accumulation of misfolded proteins in the ER and aims at restoring ER homeostasis. The ERUPR is transduced by three major ER-resident stress sensors, namely PKR-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol requiring enzyme 1 (IRE1). Activation of these ER stress sensors leads to transcriptional reprogramming of the cells. Recently, microRNAs (miRNAs), small noncoding RNAs that generally repress gene expression, have emerged as key regulators of ER homeostasis and important players in ERUPR-dependent signaling. Moreover, the miRNAs biogenesis machinery appears to also be regulated upon ER stress. Herein we extensively review the relationships existing between “canonical” ERUPR signaling, control of ER homeostasis, and miRNAs. We reveal an intricate signaling network that might confer specificity and selectivity to the ERUPR in tissue- or stress-dependent fashion. We discuss these issues in the context of the physiological and pathophysiological roles of ERUPR signaling.

scholarly journals Link between endoplasmic reticulum stress and autophagy in neurodegenerative diseases

2017 ◽  
Vol 4 (1) ◽  
Author(s):  
Toru Hosoi ◽  
Jun Nomura ◽  
Keigo Tanaka ◽  
Koichiro Ozawa ◽  
Akinori Nishi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Brain Function ◽  
Review Article ◽  
Double Stranded Rna ◽  
Unfolded Protein ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractIncreasing evidence suggests that endoplasmic reticulum (ER) stress and autophagy play an important role in regulating brain function. ER stress activates three major branches of the unfolded protein response (UPR) pathways, namely inositol-requiring enzyme-1 (IRE1), double stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) and activating transcription factor 6 (ATF6)-mediated pathways. Recent studies have suggested that these UPR signals may be linked to autophagy. In this review article, we summarize recent evidence and discuss a possible link between ER stress and autophagy with regard to neurodegenerative diseases. Furthermore, possible pharmacological strategies targeting UPR and autophagy are discussed.

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