scholarly journals Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 2. Protein misfolding and ER stress

2014 ◽  
Vol 307 (8) ◽  
pp. C657-C670 ◽  
Author(s):  
Joseph E. Chambers ◽  
Stefan J. Marciniak
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Synthesis ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Protein Misfolding ◽  
Secretory Cells ◽  
Stress Signaling ◽  
Cellular Mechanisms ◽  
Major Site ◽  
Health And Disease

The endoplasmic reticulum (ER) is a major site of protein synthesis, most strikingly in the specialized secretory cells of metazoans, which can produce their own weight in proteins daily. Cells possess a diverse machinery to ensure correct folding, assembly, and secretion of proteins from the ER. When this machinery is overwhelmed, the cell is said to experience ER stress, a result of the accumulation of unfolded or misfolded proteins in the lumen of the organelle. Here we discuss the causes of ER stress and the mechanisms by which cells elicit a response, with an emphasis on recent discoveries.

Overexpression of calreticulin fails to abolish its induction by perturbation of normal ER function

1998 ◽  
Vol 76 (5) ◽  
pp. 875-880 ◽  
Author(s):  
David H Llewellyn ◽  
H Llewelyn Roderick
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Endoplasmic Reticulum Stress ◽  
Fusion Protein ◽  
Er Stress ◽  
Hela Cells ◽  
Mammalian Cells ◽  
Stress Signaling ◽  
Glucose Response ◽  
The Stability

Along with other endoplasmic reticulum (ER) Ca2+-binding proteins, notably the glucose-response proteins grp78 and grp94, expression of calreticulin is induced in response to perturbation of normal ER function. It has yet to be clearly defined how this stress is signaled from the ER to the nucleus in mammalian cells, particularly with regard to its initiation. Using a GFP-calreticulin fusion protein, we have generated and selected stably transfected HeLa cells that overexpress calreticulin to investigate whether the protein might be involved in signaling its own induction. Basal levels of endogenous calreticulin mRNA and protein were unaffected in these cells, indicating that overexpression alone does not induce a stress response. ER stress induced calreticulin expression in response to either thapsigargin or tunicamycin was equivalent in these cells to that seen in control, nontransfected cells, leading us to conclude that calreticulin is unlikely be involved in its own induction. Levels of the mRNA encoding the fusion protein were also increased by tunicamycin, but not thapsigargin, suggesting that, in agreement with our previous observations, inhibition of N-linked glycosylation may increase the stability of calreticulin mRNA. This indicates that in mammalian cells, there is more than one signaling pathway for the ER stress response.Key words: calreticulin, endoplasmic reticulum stress, signaling.

scholarly journals Expression of Endoplasmic Reticulum Chaperones in Cardiac Development

2008 ◽  
Vol 2 (1) ◽  
pp. 31-35 ◽  
Author(s):  
Sylvia Papp ◽  
Xiaochu Zhang ◽  
Eva Szabo ◽  
Marek Michalak ◽  
Michal Opas
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Synthesis ◽  
Embryonic Development ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Cardiac Development ◽  
Large Protein ◽  
Induce Endoplasmic Reticulum Stress ◽  
Caspase 7

To determine if cardiogenesis causes endoplasmic reticulum stress, we examined chaperone expression. Many cardiac pathologies cause activation of the fetal gene program, and we asked the reverse: could activation of the fetal gene program during development induce endoplasmic reticulum stress/chaperones? We found stress related chaperones were more abundant in embryonic compared to adult hearts, indicating endoplasmic reticulum stress during normal cardiac development. To determine the degree of stress, we investigated endoplasmic reticulum stress pathways during cardiogenesis. We detected higher levels of ATF6α, caspase 7 and 12 in adult hearts. Thus, during embryonic development, there is large protein synthetic load but there is no endoplasmic reticulum stress. In adult hearts, chaperones are less abundant but there are increased levels of ATF6α and ER stress-activated caspases. Thus, protein synthesis during embryonic development does not seem to be as intense a stress as is required for apoptosis that is found during postnatal remodelling.

Testicular Injury Attenuated by Rapamycin Through Induction of Autophagy and Inhibition of Endoplasmic Reticulum Stress in Streptozotocin- Induced Diabetic Rats

2019 ◽  
Vol 19 (5) ◽  
pp. 665-675 ◽  
Author(s):  
Wenjiao Shi ◽  
Zhixin Guo ◽  
Ruixia Yuan
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Protective Effect ◽  
Er Stress ◽  
B Cell Lymphoma ◽  
Diabetic Rats ◽  
Pathological Changes ◽  
Rapamycin Treatment ◽  
Related Proteins

Background and Objective: This study investigated whether rapamycin has a protective effect on the testis of diabetic rats by regulating autophagy, endoplasmic reticulum stress, and oxidative stress. Methods: Thirty male Sprague-Dawley rats were randomly divided into three groups: control, diabetic, and diabetic treated with rapamycin, which received gavage of rapamycin (2mg.kg-1.d-1) after induction of diabetes. Diabetic rats were induced by intraperitoneal injection of streptozotocin (STZ, 65mg.Kg-1). All rats were sacrificed at the termination after 8 weeks of rapamycin treatment. The testicular pathological changes were determined by hematoxylin and eosin staining. The protein or mRNA expression of autophagy-related proteins (Beclin1, microtubule-associated protein light chain 3 (LC3), p62), ER stress marked proteins (CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), caspase-12), oxidative stress-related proteins (p22phox, nuclear factor erythroid2-related factor 2 (Nrf2)) and apoptosis-related proteins (Bax, B cell lymphoma-2 (Bcl-2)) were assayed by western blot or real-time fluorescence quantitative PCR. Results: There were significant pathological changes in the testes of diabetic rats. The expression of Beclin1, LC3, Nrf2, Bcl-2 were significantly decreased and p62, CHOP, caspase12, p22phox, and Bax were notably increased in the testis of diabetic rats (P <0.05). However, rapamycin treatment for 8 weeks significantly reversed the above changes in the testis of diabetic rats (P <0.05). Conclusion: Rapamycin appears to produce a protective effect on the testes of diabetic rats by inducing the expression of autophagy and inhibiting the expression of ER-stress, oxidative stress, and apoptosis.

scholarly journals Different Expression of Mitochondrial and Endoplasmic Reticulum Stress Genes in Epicardial Adipose Tissue Depends on Coronary Atherosclerosis

2021 ◽  
Vol 22 (9) ◽  
pp. 4538
Author(s):  
Helena Kratochvílová ◽  
Miloš Mráz ◽  
Barbora J. Kasperová ◽  
Daniel Hlaváček ◽  
Jakub Mahrík ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Cardiac Surgery ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Mrna Expression ◽  
Coronary Atherosclerosis ◽  
Stress Genes ◽  
Valvular Surgery

The aim of our study was to analyze mitochondrial and endoplasmic reticulum (ER) gene expression profiles in subcutaneous (SAT) and epicardial (EAT) adipose tissue, skeletal muscle, and myocardium in patients with and without CAD undergoing elective cardiac surgery. Thirty-eight patients, 27 with (CAD group) and 11 without CAD (noCAD group), undergoing coronary artery bypass grafting and/or valvular surgery were included in the study. EAT, SAT, intercostal skeletal muscle, and right atrium tissue and blood samples were collected at the start and end of surgery; mRNA expression of selected mitochondrial and ER stress genes was assessed using qRT-PCR. The presence of CAD was associated with decreased mRNA expression of most of the investigated mitochondrial respiratory chain genes in EAT, while no such changes were seen in SAT or other tissues. In contrast, the expression of ER stress genes did not differ between the CAD and noCAD groups in almost any tissue. Cardiac surgery further augmented mitochondrial dysfunction in EAT. In our study, CAD was associated with decreased expression of mitochondrial, but not endoplasmic reticulum stress genes in EAT. These changes may contribute to the acceleration of coronary atherosclerosis.

scholarly journals Endoplasmic Reticulum Stress Regulators: New Drug Targets for Parkinson’s Disease

2021 ◽  
pp. 1-10
Author(s):  
Vera Kovaleva ◽  
Mart Saarma
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Er Stress ◽  
Protein Misfolding ◽  
Drug Targets ◽  
Dopamine Neurons ◽  
Drug Candidates ◽  
The Unfolded Protein Response

Parkinson’s disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborisation and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2 + dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2 +-homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signalling machinery aimed at relieving of protein folding load in the ER. When UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1α) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical PD animal models. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation.

scholarly journals Fluoride Induces Endoplasmic Reticulum Stress and Inhibits Protein Synthesis and Secretion

2008 ◽  
Vol 116 (9) ◽  
pp. 1142-1146 ◽  
Author(s):  
Ramaswamy Sharma ◽  
Masahiro Tsuchiya ◽  
John D. Bartlett
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Synthesis ◽  
Endoplasmic Reticulum Stress

scholarly journals Endoplasmic reticulum stress in lung disease

2017 ◽  
Vol 26 (144) ◽  
pp. 170018 ◽  
Author(s):  
Stefan J. Marciniak
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Pulmonary Fibrosis ◽  
Endoplasmic Reticulum Stress ◽  
Lung Disease ◽  
Cigarette Smoke ◽  
Protein Misfolding ◽  
Fine Particulates ◽  
Disease Protein

Exposure to inhaled pollutants, including fine particulates and cigarette smoke is a major cause of lung disease in Europe. While it is established that inhaled pollutants have devastating effects on the genome, it is now recognised that additional effects on protein folding also drive the development of lung disease. Protein misfolding in the endoplasmic reticulum affects the pathogenesis of many diseases, ranging from pulmonary fibrosis to cancer. It is therefore important to understand how cells respond to endoplasmic reticulum stress and how this affects pulmonary tissues in disease. These insights may offer opportunities to manipulate such endoplasmic reticulum stress pathways and thereby cure lung disease.

scholarly journals RHBDL4 protects against endoplasmic reticulum stress by regulating the morphology and distribution of ER sheets

2021 ◽  
Author(s):  
Viorica Liebe Lastun ◽  
Matthew Freeman
Keyword(s):  
Cell Cycle ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Liver Steatosis ◽  
Physiological Role ◽  
Cell Types ◽  
Rhomboid Protease ◽  
Rapid Changes

In metazoans, the architecture of the endoplasmic reticulum (ER) differs between cell types, and undergoes major changes through the cell cycle and according to physiological needs. Although much is known about how the different ER morphologies are generated and maintained, especially the ER tubules, how context dependent changes in ER shape and distribution are regulated and the factors involved are less characterized. Here, we show that RHBDL4, an ER-resident rhomboid protease, modulates the shape and distribution of the ER, especially under conditions that require rapid changes in the ER sheet distribution, including ER stress. RHBDL4 interacts with CLIMP-63, a protein involved in ER sheet stabilisation, and with the cytoskeleton. Mice lacking RHBDL4 are sensitive to ER stress and develop liver steatosis, a phenotype associated with unresolved ER stress. Our data introduce a new physiological role of RHBDL4 and also imply that this function does not require its enzymatic activity.

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