scholarly journals Gut bacterial metabolites modulate endoplasmic reticulum stress

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xiaobo Ke ◽  
Kwontae You ◽  
Matthieu Pichaud ◽  
Henry J. Haiser ◽  
Daniel B. Graham ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Epithelial Cell ◽  
Er Stress ◽  
Pathogenic Bacteria ◽  
Molecular Mechanisms ◽  
Protease Inhibition ◽  
Bacterial Metabolites ◽  
Er Stress Response ◽  
Stress Pathway

Abstract Background The endoplasmic reticulum (ER) is a membranous organelle that maintains proteostasis and cellular homeostasis, controlling the fine balance between health and disease. Dysregulation of the ER stress response has been implicated in intestinal inflammation associated with inflammatory bowel disease (IBD), a chronic condition characterized by changes to the mucosa and alteration of the gut microbiota. While the microbiota and microbially derived metabolites have also been implicated in ER stress, examples of this connection remain limited to a few observations from pathogenic bacteria. Furthermore, the mechanisms underlying the effects of bacterial metabolites on ER stress signaling have not been well established. Results Utilizing an XBP1s-GFP knock-in reporter colorectal epithelial cell line, we screened 399 microbiome-related metabolites for ER stress pathway modulation. We find both ER stress response inducers (acylated dipeptide aldehydes and bisindole methane derivatives) and suppressors (soraphen A) and characterize their activities on ER stress gene transcription and translation. We further demonstrate that these molecules modulate the ER stress pathway through protease inhibition or lipid metabolism interference. Conclusions Our study identified novel links between classes of gut microbe-derived metabolites and the ER stress response, suggesting the potential for these metabolites to contribute to gut ER homeostasis and providing insight into the molecular mechanisms by which gut microbes impact intestinal epithelial cell homeostasis.

scholarly journals Endoplasmic Reticulum Stress-Related Inflammation and Cardiovascular Diseases

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Tomomi Gotoh ◽  
Motoyoshi Endo ◽  
Yuichi Oike
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Cardiovascular Diseases ◽  
Inflammatory Response ◽  
Er Stress ◽  
Er Stress Response ◽  
Stress Response Pathway ◽  
Apoptosis Pathways ◽  
Novel Target ◽  
Stress Pathway

The endoplasmic reticulum (ER) is the site of synthesis and maturation of proteins designed for secretion or for localization on the cell membrane. Various types of stress from both inside and outside cells disturb ER function, thus causing unfolded or misfolded proteins to accumulate in the ER. To improve and maintain the ER functions against such stresses, the ER stress response pathway is activated. However, when the stress is prolonged or severe, apoptosis pathways are activated to remove damaged cells. It was recently reported that the ER stress pathway is also involved in the inflammatory response, whereby inflammation induces ER stress, and ER stress induces an inflammatory response. Therefore, the ER stress response pathway is involved in various diseases, including cardiovascular diseases such as atherosclerosis and ischemic diseases, in various ways. The ER stress pathway may represent a novel target for the treatment of these diseases.

scholarly journals Sigmar1 regulates endoplasmic reticulum stress-induced C/EBP-homologous protein expression in cardiomyocytes

2017 ◽  
Vol 37 (4) ◽  
Author(s):  
Shafiul Alam ◽  
Chowdhury S. Abdullah ◽  
Richa Aishwarya ◽  
A. Wayne Orr ◽  
James Traylor ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Neonatal Rat ◽  
Cellular Toxicity ◽  
Sigma 1 Receptor ◽  
Homologous Protein ◽  
Er Stress Response ◽  
Chop Expression ◽  
Stress Pathway

C/EBP-homologous protein (CHOP) is a ubiquitously expressed stress-inducible transcription factor robustly induced by maladaptive endoplasmic reticulum (ER) stresses in a wide variety of cells. Here, we examined a novel function of Sigma 1 receptor (Sigmar1) in regulating CHOP expression under ER stress in cardiomyocytes. We also defined Sigmar1-dependent activation of the adaptive ER-stress pathway in regulating CHOP expression. We used adenovirus-mediated Sigmar1 overexpression as well as Sigmar1 knockdown by siRNA in neonatal rat ventricular cardiomyocytes (NRCs); to induce ER stress, cardiomyocytes were treated with tunicamycin. Sigmar1-siRNA knockdown significantly increased the expression of CHOP and significantly induced cellular toxicity by sustained activation of ER stress in cardiomyocytes. Sigmar1 overexpression decreased the expression of CHOP and significantly decreased cellular toxicity in cells. Using biochemical and immunocytochemical experiments, we also defined the specific ER-stress pathway associated with Sigmar1-dependent regulation of CHOP expression and cellular toxicity. We found that Sigmar1 overexpression significantly increased inositol requiring kinase 1α (IRE1α) phosphorylation and increased spliced X-box-binding proteins (XBP1s) expression as well as nuclear localization. In contrast, Sigmar1 knockdown significantly decreased IRE1α phosphorylation and decreased XBP1s expression as well as nuclear transport. Taken together, these results indicate that Sigmar1-dependent activation of IRE1α-XBP1s ER-stress response pathways are associated with inhibition of CHOP expression and suppression of cellular toxicity. Hence, Sigmar1 is an essential component of the adaptive ER-stress response pathways eliciting cellular protection in cardiomyocytes.

scholarly journals Cold storage induces rat liver pyroptosis by activating endoplasmic reticulum stress response through the ATF6-CHOP pathway

2021 ◽  
Author(s):  
jiang liu ◽  
Tiancheng Liang ◽  
Yong Ni ◽  
De Luo ◽  
Bo Li ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Liver Injury ◽  
Er Stress ◽  
Rat Liver ◽  
Cold Storage ◽  
Liver Tissue ◽  
Molecular Mechanisms ◽  
Er Stress Response ◽  
Caspase 1

Abstract Aims :Liver injury is a common complication of cold storage (CS), and often constitutes a direct cause for liver transplantation failure. The cellular and molecular mechanisms underlying CS-induced liver injury remain unclear. Recent evidence indicates that pyroptosis plays an important role in multiple pathophysiological processes. Using rat liver tissue and cells as a model, we identified a novel mechanism by which inflammasome-dependent interleukin-1β (IL-1β) activation and hepatocyte pyroptosis mediate CS-induced liver injury.Methods :To induce CS, liver tissue and cells were subjected to storage at 4ºC for 12 and 24 h. Inhibition of endoplasmic reticulum (ER) stress was achieved by RNA silencing. Measurements of caspase-1, caspase-11, and IL-1β were performed.Results: Pyroptosis was activated in CS-treated livers, as evidenced by increased levels of caspase-1 and caspase-11 activity, and the elevated expression of IL-1β. ER stress response was activated as well. Inhibition of ER stress response prevented CS-induced liver pyroptosis and inflammation.Conclusion : Our findings suggest that pyroptosis might be playing an important role in the development of liver injury induced by CS. Overactivated ER stress response, followed by activation of the ATF6-CHOP signaling pathway, might be a novel molecular mechanism involved in CS-induced pyroptosis of liver tissue and cells.

scholarly journals Endoplasmic reticulum stress in glomerular epithelial cell injury

2011 ◽  
Vol 301 (3) ◽  
pp. F496-F508 ◽  
Author(s):  
Andrey V. Cybulsky ◽  
Tomoko Takano ◽  
Joan Papillon ◽  
Thomas M. Kitzler ◽  
Krikor Bijian
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Epithelial Cell ◽  
Er Stress ◽  
Cell Injury ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Glomerular Epithelial Cell ◽  
Er Stress Response

Focal segmental glomerulosclerosis (FSGS) may be associated with glomerular epithelial cell (GEC; podocyte) apoptosis due to acquired injury or mutations in specific podocyte proteins. This study addresses mediation of GEC injury, focusing on endoplasmic reticulum (ER) stress. We studied signaling in cultured GECs in the presence or absence of the extracellular matrix (ECM). Adhesion to collagen supports cell survival, but adhesion to plastic (loss of contact with ECM) leads to apoptosis. Compared with collagen-adherent cells, GECs on plastic showed increased protein misfolding in the ER, and an adaptive-protective ER stress response, including increased expression of ER chaperones, increased phosphorylation of eukaryotic translation initiation factor-2α (eIF2α), and a reduction in protein synthesis. Activation of these ER stress pathways counteracted apoptosis. However, tunicamycin (a potent stimulator of ER stress) changed the ER stress response from protective to cytotoxic, as tunicamycin induced the proapoptotic ER stress gene, C/EBP homologous protein-10, and exacerbated apoptosis in GECs adherent to plastic, but not collagen. In GECs adherent to plastic, adaptive ER stress was associated with an increase in polyubiquitinated proteins and “choking” of the proteasome. Furthermore, pharmacological inhibition of the proteasome induced ER stress in GECs. Finally, we show that ER stress (induction of ER chaperones and eIF2α phosphorylation) was evident in experimental FSGS in vivo. Thus interactions of GECs with ECM may regulate protein folding and induction of the ER stress response. FSGS is associated with induction of ER stress. Enhancing protective aspects of the ER stress response may reduce apoptosis and possibly glomerulosclerosis.

scholarly journals Critical review: involvement of endoplasmic reticulum stress in the aetiology of Alzheimer's disease

Open Biology ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 180024 ◽  
Author(s):  
Shoko Hashimoto ◽  
Takaomi C. Saido
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Mouse Models ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
Neuronal Cell ◽  
Er Stress Response

The endoplasmic reticulum (ER) stress response is regarded as an important process in the aetiology of Alzheimer's disease (AD). The accumulation of pathogenic misfolded proteins and the disruption of intracellular calcium (Ca 2+ ) signalling are considered to be fundamental mechanisms that underlie the induction of ER stress, leading to neuronal cell death. Indeed, a number of studies have proposed molecular mechanisms linking ER stress to AD pathogenesis based on results from in vitro systems and AD mouse models. However, stress responsivity was largely different between each mouse model, even though all of these models display AD-related pathologies. While several reports have shown elevated ER stress responses in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (Tg) AD mouse models, we and other groups, in contrast, observed no such ER stress response in APP-single-Tg or App -knockin mice. Therefore, it is debatable whether the ER stress observed in APP and PS1 double-Tg mice is due to AD pathology. From these findings, the roles of ER stress in AD pathogenesis needs to be carefully addressed in future studies. In this review, we summarize research detailing the relationship between ER stress and AD, and analyse the results in detail.

scholarly journals Differential regulation of the endoplasmic reticulum stress response in pancreatic β-cells exposed to long-chain saturated and monounsaturated fatty acids

2008 ◽  
Vol 197 (3) ◽  
pp. 553-563 ◽  
Author(s):  
Eleftheria Diakogiannaki ◽  
Hannah J Welters ◽  
Noel G Morgan
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Initiation Factor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Er Stress Response ◽  
Stress Pathway ◽  
Long Chain

Exposure of pancreatic β-cells to long-chain fatty acids leads to the activation of some components of the endoplasmic reticulum (ER) stress pathway and this mechanism may underlie the ability of certain fatty acids to promote β-cell death. We have studied ER stress in BRIN-BD11 β-cells exposed to either the saturated fatty acid palmitate (C16:0) or the monounsaturated palmitoleate (C16:1). Palmitate (0.025–0.25 mM) induced the expression of various markers of the RNA-dependent protein kinase-like ER eukaryotic initiation factor 2α (eIF2α) kinase (PERK)-dependent pathway of ER stress (phospho-eIF2α; ATF4, activating transcription factor 4 and C/EBP homologous protein (CHOP-10)) although it failed to promote the expression of the ER chaperone GRP78. By contrast, palmitoleate did not induce any markers of the ER stress pathway even at concentrations as high as 1 mM. When palmitate and palmitoleate were added in combination, a marked attenuation of the ER stress response occurred. Under these conditions, the levels of phospho-eIF2α, ATF4 and CHOP-10 were reduced to less than those found in control cells. Palmitoleate also attenuated the ER stress response to the protein glycosylation inhibitor, tunicamycin, and improved the viability of the cells exposed to this agent. Exposure of the BRIN-BD11 cells to the protein phosphatase inhibitor, salubrinal, in the absence of fatty acids resulted in increased eIF2α phosphorylation but this was abolished by co-incubation with palmitoleate. We conclude that saturated fatty acids activate components of the PERK-dependent ER stress pathway in β-cells, ultimately leading to increased apoptosis. This effect is antagonised by monounsaturates that may exert their anti-apoptotic actions by regulating the activity of one or more kinase enzymes involved in mediating the phosphorylation of eIF2α.

scholarly journals NOD1/NOD2 and RIP2 Regulate Endoplasmic Reticulum Stress-Induced Inflammation during Chlamydia Infection

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Oanh H. Pham ◽  
Bokyung Lee ◽  
Jasmine Labuda ◽  
A. Marijke Keestra-Gounder ◽  
Mariana X. Byndloss ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Inflammatory Response ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Young Women ◽  
The United States ◽  
Chlamydia Infection ◽  
Er Stress Response

ABSTRACT The inflammatory response to Chlamydia infection is likely to be multifactorial and involve a variety of ligand-dependent and -independent recognition pathways. We previously reported the presence of NOD1/NOD2-dependent endoplasmic reticulum (ER) stress-induced inflammation during Chlamydia muridarum infection in vitro, but the relevance of this finding to an in vivo context is unclear. Here, we examined the ER stress response to in vivo Chlamydia infection. The induction of interleukin 6 (IL-6) production after systemic Chlamydia infection correlated with expression of ER stress response genes. Furthermore, when tauroursodeoxycholate (TUDCA) was used to inhibit the ER stress response, an increased bacterial burden was detected, suggesting that ER stress-driven inflammation can contribute to systemic bacterial clearance. Mice lacking both NOD1 and NOD2 or RIP2 exhibited slightly higher systemic bacterial burdens after infection with Chlamydia. Overall, these data suggest a model where RIP2 and NOD1/NOD2 proteins link ER stress responses with the induction of Chlamydia-specific inflammatory responses. IMPORTANCE Understanding the initiation of the inflammatory response during Chlamydia infection is of public health importance given the impact of this disease on young women in the United States. Many young women are chronically infected with Chlamydia but are asymptomatic and therefore do not seek treatment, leaving them at risk of long-term reproductive harm due to inflammation in response to infection. Our manuscript explores the role of the endoplasmic reticulum stress response pathway initiated by an innate receptor in the development of this inflammation.

scholarly journals Endoplasmic Reticulum (ER) Stress Response Failure in Diseases

2020 ◽  
Vol 30 (9) ◽  
pp. 672-675 ◽  
Author(s):  
Kashi Raj Bhattarai ◽  
Manoj Chaudhary ◽  
Hyung-Ryong Kim ◽  
Han-Jung Chae
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Er Stress Response

scholarly journals Endoplasmic reticulum stress response in the roadway for the effects of non-steroidal anti-inflammatory drugs

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Fernanda L.B. Mügge ◽  
Aristóbolo M. Silva
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Stress Responses ◽  
Endoplasmic Reticulum Stress Response ◽  
The Road ◽  
Er Stress Response ◽  
Mediated Effects ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

AbstractOver the past decade, a handful of evidence has been provided that nonsteroidal anti-inflammatory drugs (NSAIDs) display effects on the homeostasis of the endoplasmic reticulum (ER). Their uptake into cells will eventually lead to activation or inhibition of key molecules that mediate ER stress responses, raising not only a growing interest for a pharmacological target in ER stress responses but also important questions how the ER-stress mediated effects induced by NSAIDs could be therapeutically advantageous or not. We review here the toxicity effects and therapeutic applications of NSAIDs involving the three majors ER stress arms namely PERK, IRE1, and ATF6. First, we provide brief introduction on the well-established and characterized downstream events mediated by these ER stress players, followed by presentation of the NSAIDs compounds and mode of action, and finally their effects on ER stress response. NSAIDs present promising drug agents targeting the components of ER stress in different aspects of cancer and other diseases, but a better comprehension of the mechanisms underlying their benefits and harms will certainly pave the road for several diseases’ therapy.

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