scholarly journals Aging alters the metabolic flux signature of the ER unfolded protein response in vivo in mice

2021 ◽  
Author(s):  
Catherine P Schneider ◽  
Lucy Peng ◽  
Sam Yuen ◽  
John Halstead ◽  
Hector Palacios ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Mrna Levels ◽  
Aged Mice ◽  
Unfolded Protein ◽  
Protein Response ◽  
Young Mice

Age is a risk factor for numerous diseases, including neurodegenerative diseases, cancers, and diabetes. Loss of protein homeostasis is a central hallmark of aging. Activation of the endoplasmic reticulum unfolded protein response (UPRER) includes changes in protein translation and membrane lipid synthesis. Using stable isotope labeling, a signature of the UPRER in vivo in mouse liver was developed by inducing ER stress and measuring rates of both proteome-wide translation and de novo lipogenesis. Several changes in protein synthesis across ontologies were noted with age, including a more dramatic suppression of translation under ER stress in aged mice as compared to young mice. Binding immunoglobulin protein (BiP) synthesis rates and mRNA levels were increased more in aged than young mice. De novo lipogenesis rates decreased under ER stress conditions in aged mice, including both triglyceride and phospholipid fractions. In young mice, only a significant reduction was seen in the triglyceride fraction. These data indicate that aged mice have an exaggerated response to ER stress, which may indicate that the aging renders the UPRER less effective in resolving proteotoxic stress.

scholarly journals Interaction of Diet with the Metabolic Flux Signatures of the Unfolded Protein Response

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 697-697
Author(s):  
Catherine Schneider ◽  
Marc Hellerstein
Keyword(s):  
Fatty Acids ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Metabolic Flux ◽  
Unsaturated Fatty Acids ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Objectives Endoplasmic reticulum (ER) stress is involved in the progression of several diseases, including diet and obesity-related conditions such as nonalcoholic fatty liver disease. Our goal was to understand the role of diet on the unfolded protein response (UPR), an important pathway in ER stress response, in efforts to elucidate the role of the UPR in the progression to non-alcoholic fatty liver disease. Methods We used stable isotope labeling with tandem mass spectrometric analysis to characterize proteome-wide synthesis rates and de novo lipogenesis rates in vivo in mouse liver to generate metabolic flux signatures of the unfolded protein response. We initiated the unfolded protein response through treatment with tunicamycin. Diets rich in either unsaturated, oleic, acids, or saturated, palmitic, acids were given to mice for five weeks to determine the effect of dietary fatty acids on this induced ER stress response. Results With induction of the unfolded protein response, we observed reduced protein synthesis across most ontologies, but increased synthesis of ER proteins and chaperones. We also found reduced de novo lipogenesis after 48 and 72 hours of induced ER stress. Reduction in food intake and significant weight loss also occurred after 48 and 72 hours. Electron microscopy revealed striking morphological differences in the ER and accumulation of lipid droplets with ER stress. Diets high in unsaturated fatty acids had a lesser impact on the progression of the unfolded protein response. Conclusions These data begin to characterize how the unfolded protein response progresses over time, and the metabolic changes that occur with ER stress. Diets rich in saturated or unsaturated fatty acids had different effects on the metabolic signatures of the UPR, suggesting the type dietary fatty acid is important in properly handling ER stress. Funding Sources NIH.

scholarly journals Unfolded Protein Response and Crohn’s Diseases: A Molecular Mechanism of Wound Healing in the Gut

2021 ◽  
Author(s):  
Chao Li
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Immune Cell ◽  
Macrophage Polarization ◽  
Intestinal Epithelial ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Endoplasmic reticulum (ER) stress triggers a series of signaling and transcriptional events termed the unfolded protein response (UPR). Severe ER stress is associated with the development of fibrosis in different organs including lung, liver, kidney, heart, and intestine. ER stress is an essential response of epithelial and immune cells in the pathogenesis of inflammatory bowel disease (IBD) including Crohn’s disease. Intestinal epithelial cells are susceptible to ER stress-mediated damage due to secretion of a large amount of proteins that are involved in mucosal defense. In other cells, ER stress is linked to myofibroblast activation, extracellular matrix production, macrophage polarization, and immune cell differentiation. This review focuses on the role of UPR in the pathogenesis in IBD from an immunologic perspective. The roles of macrophage and mesenchymal cells in the UPR from in vitro and in vivo animal models are discussed. The links between ER stress and other signaling pathways such as senescence and autophagy are introduced. Recent advances in the understanding of the epigenetic regulation of UPR signaling are also updated here. The future directions of development of the UPR research and therapeutic strategies to manipulate ER stress levels are also reviewed.

scholarly journals Activation of the IRE1α Arm, but not the PERK Arm, of the Unfolded Protein Response Contributes to Fumonisin B1-Induced Hepatotoxicity

Toxins ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 55 ◽  
Author(s):  
Xiaoyi Liu ◽  
Enxiang Zhang ◽  
Shutao Yin ◽  
Chong Zhao ◽  
Lihong Fan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Liver Toxicity ◽  
Fumonisin B1 ◽  
Critical Event ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Previous studies by us or others have shown that endoplasmic reticulum (ER) stress was activated by fumonisin 1 (FB1) exposure, which is considered to be a critical event in the FB1-induced toxic effect. However, the detailed mechanisms underlying FB1-induced ER stress-mediated liver toxicity remain elusive. The objectives of the present study were designed to address the following issues: (1) the contribution of each arm of the unfolded protein response (UPR); (2) the downstream targets of ER stress that mediated FB1-induced liver toxicity; and (3) the relationship between ER stress and oxidative stress triggered by FB1. We also investigated whether the inhibition of ER stress by its inhibitor could offer protection against FB1-induced hepatotoxicity in vivo, which has not been critically addressed previously. The results showed that the activation of the IRE1α axis, but not of the PERK axis, of UPR contributed to FB1-induced ER stress-mediated hepatocyte toxicity; the activation of the Bax/Bak-mediated mitochondrial pathway lay downstream of IRE1α to trigger mitochondrial-dependent apoptosis in response to FB1; FB1-induced oxidative stress and ER stress augmented each other through a positive feedback mechanism; tauroursodeoxycholic acid (TUDCA)-mediated ER stress inactivation is an effective approach to counteract FB1-induced hepatotoxicity in vivo. The data of the present study allow us to better understand the mechanisms of FB1-induced hepatotoxicity.

scholarly journals Dominant negative FADD dissipates the proapoptotic signalosome of the unfolded protein response in diabetic embryopathy

2015 ◽  
Vol 309 (10) ◽  
pp. E861-E873 ◽  
Author(s):  
Fang Wang ◽  
Hongbo Weng ◽  
Michael J. Quon ◽  
Jingwen Yu ◽  
Jian-Ying Wang ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
High Glucose ◽  
Dominant Negative ◽  
Caspase 8 ◽  
Death Domain ◽  
Unfolded Protein ◽  
Protein Response

Endoplasmic reticulum (ER) stress and caspase 8-dependent apoptosis are two interlinked causal events in maternal diabetes-induced neural tube defects (NTDs). The inositol-requiring enzyme 1α (IRE1α) signalosome mediates the proapoptotic effect of ER stress. Diabetes increases tumor necrosis factor receptor type 1R-associated death domain (TRADD) expression. Here, we revealed two new unfolded protein response (UPR) regulators, TRADD and Fas-associated protein with death domain (FADD). TRADD interacted with both the IRE1α-TRAF2-ASK1 complex and FADD. In vivo overexpression of a FADD dominant negative (FADD-DN) mutant lacking the death effector domain disrupted diabetes-induced IRE1α signalosome and suppressed ER stress and caspase 8-dependent apoptosis, leading to NTD prevention. FADD-DN abrogated ER stress markers and blocked the JNK1/2-ASK1 pathway. Diabetes-induced mitochondrial translocation of proapoptotic Bcl-2 members mitochondrial dysfunction and caspase cleavage were also alleviated by FADD-DN. In vitro TRADD overexpression triggered UPR and ER stress before manifestation of caspase 3 and caspase 8 cleavage and apoptosis. FADD-DN overexpression repressed high glucose- or TRADD overexpression-induced IRE1α phosphorylation, its downstream proapoptotic kinase activation and endonuclease activities, and apoptosis. FADD-DN also attenuated tunicamycin-induced UPR and ER stress. These findings suggest that TRADD participates in the IRE1α signalosome and induces UPR and ER stress and that the association between TRADD and FADD is essential for diabetes- or high glucose-induced UPR and ER stress.

scholarly journals Unfolded Protein Response and Crohn’s Diseases: A Molecular Mechanism of Wound Healing in the Gut

2021 ◽  
Vol 3 (1) ◽  
pp. 31-43
Author(s):  
Chao Li
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Immune Cell ◽  
Macrophage Polarization ◽  
Intestinal Epithelial ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Endoplasmic reticulum (ER) stress triggers a series of signaling and transcriptional events termed the unfolded protein response (UPR). Severe ER stress is associated with the development of fibrosis in different organs, including lung, liver, kidney, heart, and intestine. ER stress is an essential response of epithelial and immune cells in the pathogenesis of Inflammatory Bowel Disease (IBD), including Crohn’s disease (CD). Intestinal epithelial cells are susceptible to ER stress-mediated damage due to secretion of a large amount of proteins that are involved in mucosal defense. In other cells, ER stress is linked to myofibroblast activation, extracellular matrix production, macrophage polarization, and immune cell differentiation. This review focuses on the role of the UPR in the pathogenesis in IBD from an immunologic perspective. The roles of macrophage and mesenchymal cells in the UPR from in vitro and in vivo animal models are discussed. The links between ER stress and other signaling pathways, such as senescence and autophagy, are introduced. Recent advances in the understanding of the epigenetic regulation of the UPR signaling are also updated here. The future directions of development of the UPR research and therapeutic strategies to manipulate ER stress levels are also reviewed.

scholarly journals The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS

2021 ◽  
Vol 15 ◽  
Author(s):  
Ruxandra Dafinca ◽  
Paola Barbagallo ◽  
Kevin Talbot
Keyword(s):  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Unfolded Protein Response ◽  
Nucleocytoplasmic Transport ◽  
Cellular Processes ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the motor system with complex determinants, including genetic and non-genetic factors. Despite this heterogeneity, a key pathological signature is the mislocalization and aggregation of specific proteins in the cytoplasm, suggesting that convergent pathogenic mechanisms focusing on disturbances in proteostasis are important in ALS. In addition, many cellular processes have been identified as potentially contributing to disease initiation and progression, such as defects in axonal transport, autophagy, nucleocytoplasmic transport, ER stress, calcium metabolism, the unfolded protein response and mitochondrial function. Here we review the evidence from in vitro and in vivo models of C9ORF72 and TDP-43-related ALS supporting a central role in pathogenesis for endoplasmic reticulum stress, which activates an unfolded protein response (UPR), and mitochondrial dysfunction. Disruption in the finely tuned signaling between the ER and mitochondria through calcium ions may be a crucial trigger of mitochondrial deficits and initiate an apoptotic signaling cascade, thus acting as a point of convergence for multiple upstream disturbances of cellular homeostasis and constituting a potentially important therapeutic target.

scholarly journals Metabolic flux signatures of the ER unfolded protein response in vivo reveal decreased hepatic de novo lipogenesis and mobilization of lipids from adipose tissue to liver

2020 ◽  
Author(s):  
Catherine P. Schneider ◽  
Lucy Peng ◽  
Samuel Yuen ◽  
Michael Chang ◽  
Rozalina Karapetyan ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Liver Disease ◽  
Fatty Liver ◽  
Er Stress ◽  
Fatty Liver Disease ◽  
Metabolic Flux ◽  
De Novo ◽  
Unfolded Protein ◽  
Protein Response

AbstractThe unfolded protein response in the endoplasmic reticulum (UPRER) is involved in a number of metabolic diseases, including non-alcoholic fatty liver disease. Here, we characterize the UPRER induced metabolic changes in mouse liver through in vivo metabolic labeling and mass spectrometric analysis of proteome and lipid fluxes. We induced ER stress in vivo via tunicamycin treatment and measured rates of proteome-wide protein synthesis, de novo lipogenesis and cholesterol synthesis serially over a three-day period, thereby generating a metabolic “signature” of the UPRER over time. Synthesis of most proteins was suppressed under ER stress conditions, including proteins involved in lipogenesis, consistent with reduced de novo lipogenesis at 48 and 72 hours. Electron microscopy revealed striking morphological changes to ER and H&E staining showed lipid droplet enriched livers under ER stress. Pre-labeling of adipose tissue prior to ER stress induction revealed mobilization of lipids from adipose to the liver. Interestingly, the source of these lipids was uptake of free fatty acids, not whole triglycerides or phospholipids from lipoproteins, as demonstrated by replacement of the triglyceride-glycerol moiety in liver concurrently with increased incorporation of labeled palmitate from adipose. We also induced ER stress by a high-fat diet and observed similar metabolic flux signatures, suggesting that this mechanism may play a role in the progression of fatty liver disease. This flux-based approach provides a powerful tool to identify novel regulators of ER stress and potential targets for pharmacological intervention.

scholarly journals Bax and Bak jointly control survival and dampen the early unfolded protein response in pancreatic β-cells under glucolipotoxic stress

2019 ◽  
Author(s):  
Sarah A. White ◽  
Lisa Zhang ◽  
Yu Hsuan Carol Yang ◽  
Dan S. Luciani
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Unfolded Protein ◽  
Protein Response

ABSTRACTER stress and apoptosis contribute to the loss of pancreatic β-cells under the pro-diabetic conditions of glucolipotoxicity. Although activation of the canonical pathway of intrinsic apoptosis is known to require Bax and Bak, their individual and combined involvement in glucolipotoxic β-cell death have not been demonstrated. It has also remained an open question if Bax and Bak in β-cells have non-apoptotic roles in mitochondrial function and ER stress signaling, as suggested in other cell types. Using mice with individual or combined β-cell deletion of Bax and Bak, we demonstrated that glucolipotoxic β-cell death in vitro happens in sequential stages; first via non-apoptotic mechanisms and later by apoptosis, which Bax and Bak were redundant in triggering. In contrast, they had non-redundant roles in mediating staurosporine-induced β-cell apoptosis. We further established that Bax and Bak do not affect normal glucose-stimulated β-cell Ca2+ responses, insulin secretion, or in vivo glucose tolerance. Finally, our experiments revealed that Bax and Bak together dampen the unfolded protein response in β-cells during the early stages of chemical- or glucolipotoxicity-induced ER stress. These findings identify novel roles of the canonical apoptosis machinery in modulating stress signals that are important for the pathobiology of β-cells in diabetes.

scholarly journals MANF regulates unfolded protein response and neuronal survival through its ER-located receptor IRE1α

2020 ◽  
Author(s):  
Vera Kovaleva ◽  
Li-Ying Yu ◽  
Larisa Ivanova ◽  
Jinhan Nam ◽  
Ave Eesmaa ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Neuronal Cell ◽  
Direct Interaction ◽  
Cell Types ◽  
Dopamine Neurons ◽  
Unfolded Protein ◽  
Protein Response

AbstractMesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-located protein with cytoprotective effects in numerous cell types in vitro and in models of neurodegeneration and diabetes in vivo. So far, the exact mode of its action has remained elusive and plasma membrane or ER-located receptors of MANF have not been identified. We have found that MANF can directly interact with transmembrane unfolded protein response (UPR) receptor IRE1α and compete with the major ER chaperone BiP (GRP78) for the interaction with IRE1α. With lower affinities MANF can also interact with other UPR receptors, PERK and ATF6. Using molecular modeling and mutagenesis analysis, we have identified the exact structural MANF regions involved in its binding to the luminal domain of IRE1α. MANF attenuates UPR signaling by decreasing IRE1α oligomerization and IRE1α phosphorylation. MANF mutant deficient in IRE1α binding cannot regulate IRE1α oligomerization and fails to protect neurons from ER stress induced death. Importantly, we found that MANF-IRE1α interaction is also crucial for the survival promoting action of MANF for dopamine neurons in an animal model of Parkinson’s disease. Our data reveal a novel mechanism of IRE1α regulation during ER stress and demonstrate the intracellular mode of action of MANF as a modulator of UPR and neuronal cell survival through the direct interaction with IRE1α and regulation of its activity. Furthermore, our data explain why MANF in contrast to other growth factors has no effects on naive cells and rescues only ER stressed or injured cells.

Unfolded Protein Response and Crohn’s Diseases: A Molecular Mechanism of Wound Healing in the Gut

2020 ◽  
Author(s):  
Chao Li
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Immune Cell ◽  
Macrophage Polarization ◽  
Intestinal Epithelial ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Endoplasmic reticulum (ER) stress triggers a series of signaling and transcriptional events termed the unfolded protein response (UPR). Severe ER stress is associated with the development of fibrosis in different organs including lung, liver, kidney, heart, and intestine. ER stress is an essential response of epithelial and immune cells in the pathogenesis of inflammatory bowel disease (IBD) including Crohn’s disease. Intestinal epithelial cells are susceptible to ER stress-mediated damage due to secretion of a large amount of proteins that are involved in mucosal defense. In other cells, ER stress is linked to myofibroblast activation, extracellular matrix production, macrophage polarization, and immune cell differentiation. This review focuses on the role of UPR in the pathogenesis in IBD from immunologic perspective. The roles of macrophage and mesenchymal cells in the UPR from in vitro and in vivo animal models are discussed. The links between ER stress and other signaling pathways such as senescence and autophagy are introduced. Recent advances in the understanding of the epigenetic regulation of UPR signaling are reported. The future directions of the development of the UPR research and therapeutic strategies to manipulate ER stress levels are also reviewed.

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