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 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 Effectors Targeting the Unfolded Protein Response during Intracellular Bacterial Infection

2021 ◽  
Vol 9 (4) ◽  
pp. 705
Author(s):  
Manal H. Alshareef ◽  
Elizabeth L. Hartland ◽  
Kathleen McCaffrey
Keyword(s):  
Bacterial Infection ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Host Defense ◽  
Effector Proteins ◽  
Dual Nature ◽  
Unfolded Protein ◽  
Bacterial Replication ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is a homeostatic response to endoplasmic reticulum (ER) stress within eukaryotic cells. The UPR initiates transcriptional and post-transcriptional programs to resolve ER stress; or, if ER stress is severe or prolonged, initiates apoptosis. ER stress is a common feature of bacterial infection although the role of the UPR in host defense is only beginning to be understood. While the UPR is important for host defense against pore-forming toxins produced by some bacteria, other bacterial effector proteins hijack the UPR through the activity of translocated effector proteins that facilitate intracellular survival and proliferation. UPR-mediated apoptosis can limit bacterial replication but also often contributes to tissue damage and disease. Here, we discuss the dual nature of the UPR during infection and the implications of UPR activation or inhibition for inflammation and immunity as illustrated by different bacterial pathogens.

scholarly journals Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

2021 ◽  
Vol 22 (5) ◽  
pp. 2567
Author(s):  
Yann S. Gallot ◽  
Kyle R. Bohnert
Keyword(s):  
Skeletal Muscle ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Smooth Endoplasmic Reticulum ◽  
Skeletal Muscle Atrophy ◽  
Unfolded Protein ◽  
The Individual ◽  
The Unfolded Protein Response ◽  
Protein Response

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.

Sequencing of Argonaute-bound miRNA/mRNA hybrids reveals regulation of the unfolded protein response by microRNA-320a

2021 ◽  
Author(s):  
Christopher J Fields ◽  
Lu Li ◽  
Nicholas M Hiers ◽  
Tianqi Li ◽  
Peike Sheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Cancer Cells ◽  
Rna Polymerase Ii ◽  
Mirna Biogenesis ◽  
Unfolded Protein ◽  
Colorectal Cancer Cells ◽  
The Unfolded Protein Response ◽  
Protein Response

MicroRNAs (miRNA) are short non-coding RNAs widely implicated in gene regulation. Most metazoan miRNAs utilize the RNase III enzymes Drosha and Dicer for biogenesis. One notable exception is the RNA polymerase II transcription start sites (TSS) miRNAs whose biogenesis does not require Drosha. The functional importance of the TSS-miRNA biogenesis is uncertain. To better understand the function of TSS-miRNAs, we applied a modified Crosslinking, Ligation, and Sequencing of Hybrids on Argonaute (AGO-qCLASH) to identify the targets for TSS-miRNAs in HCT116 colorectal cancer cells with or without DROSHA knockout. We observed that miR-320a hybrids dominate in TSS-miRNA hybrids identified by AGO-qCLASH. Targets for miR-320a are enriched in the eIF2 signaling pathway, a downstream component of the unfolded protein response. Consistently, in miR-320a mimic- and antagomir- transfected cells, differentially expressed genes are enriched in eIF2 signaling. Within the AGO-qCLASH data, we identified the endoplasmic reticulum (ER) chaperone Calnexin as a direct miR-320a target, thus connecting miR-320a to the unfolded protein response. During ER stress, but not amino acid deprivation, miR-320a up-regulates ATF4, a critical transcription factor for resolving ER stress. Our study investigates the targetome of the TSS-miRNAs in colorectal cancer cells and establishes miR-320a as a regulator of unfolded protein response.

scholarly journals The unfolded protein response in fission yeast modulates stability of select mRNAs to maintain protein homeostasis

eLife ◽  
2012 ◽  
Vol 1 ◽  
Author(s):  
Philipp Kimmig ◽  
Marcy Diaz ◽  
Jiashun Zheng ◽  
Christopher C Williams ◽  
Alexander Lang ◽  
...  
Keyword(s):  
Er Stress ◽  
Fission Yeast ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Er Chaperone ◽  
Stress Sensing ◽  
Transcription Activators ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Selective Decay

The unfolded protein response (UPR) monitors the protein folding capacity of the endoplasmic reticulum (ER). In all organisms analyzed to date, the UPR drives transcriptional programs that allow cells to cope with ER stress. The non-conventional splicing of Hac1 (yeasts) and XBP1 (metazoans) mRNA, encoding orthologous UPR transcription activators, is conserved and dependent on Ire1, an ER membrane-resident kinase/endoribonuclease. We found that the fission yeast Schizosaccharomyces pombe lacks both a Hac1/XBP1 ortholog and a UPR-dependent-transcriptional-program. Instead, Ire1 initiates the selective decay of a subset of ER-localized-mRNAs that is required to survive ER stress. We identified Bip1 mRNA, encoding a major ER-chaperone, as the sole mRNA cleaved upon Ire1 activation that escapes decay. Instead, truncation of its 3′ UTR, including loss of its polyA tail, stabilized Bip1 mRNA, resulting in increased Bip1 translation. Thus, S. pombe uses a universally conserved stress-sensing machinery in novel ways to maintain homeostasis in the ER.

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