The Impact of the Unfolded Protein Response and the Hexosamine Biosynthetic Pathway on Glycosylation

2017 ◽  
Vol 6 ◽  
Keyword(s):  
Unfolded Protein Response ◽  
Biosynthetic Pathway ◽  
Hexosamine Biosynthetic Pathway ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
The Impact

Abstract 261: Robust Cardioprotection Afforded by a Previously Unrecognized Link between the Unfolded Protein Response and the Hexosamine Biosynthetic Pathway

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Zhao V Wang ◽  
Yingfeng Deng ◽  
Ningguo Gao ◽  
Zully Pedrozo ◽  
Dan Li ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Biosynthetic Pathway ◽  
Ischemia Reperfusion ◽  
Uridine Diphosphate ◽  
Hexosamine Biosynthetic Pathway ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Rate Limiting

Background: The hexosamine biosynthetic pathway (HBP) generates UDP-GlcNAc (uridine diphosphate N-acetylglucosamine) for glycan synthesis and O-linked GlcNAc (O-GlcNAc) protein modifications. Despite the established role of the HBP in glucose metabolism and multiple diseases, regulation of the HBP remains largely undefined. Methods & Results: Here, we show that spliced Xbp1 (Xbp1s), the most conserved signal transducer of the unfolded protein response (UPR), is a direct transcriptional activator of the HBP. We demonstrate that the UPR triggers activation of the HBP by means of Xbp1s-dependent transcription of genes coding for key, rate-limiting enzymes. We establish that this previously unrecognized UPR-HBP axis is triggered in a variety of stress conditions known to promote O-GlcNAc modification. We go on to demonstrate that Xbp1s, acutely stimulated by ischemia/reperfusion (I/R) in heart, confers robust cardioprotection against I/R injury. We also show that HBP induction is required for this cardioprotective response. Mechanistically, HBP may mediate the adaptive branch of the UPR by activating autophagy and ER-associated degradation. Conclusion: These studies reveal that Xbp1s couples the UPR to the HBP, promoting robust cardioprotection during I/R.

scholarly journals Spliced X-Box Binding Protein 1 Couples the Unfolded Protein Response to Hexosamine Biosynthetic Pathway

Cell ◽  
2014 ◽  
Vol 156 (6) ◽  
pp. 1179-1192 ◽  
Author(s):  
Zhao V. Wang ◽  
Yingfeng Deng ◽  
Ningguo Gao ◽  
Zully Pedrozo ◽  
Dan L. Li ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Biosynthetic Pathway ◽  
Binding Protein ◽  
Hexosamine Biosynthetic Pathway ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

scholarly journals The impact of the unfolded protein response on human disease

2012 ◽  
Vol 197 (7) ◽  
pp. 857-867 ◽  
Author(s):  
Shiyu Wang ◽  
Randal J. Kaufman
Keyword(s):  
Unfolded Protein Response ◽  
Human Disease ◽  
Intracellular Signaling ◽  
Central Function ◽  
Intracellular Signaling Pathway ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis ◽  
The Impact

A central function of the endoplasmic reticulum (ER) is to coordinate protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/unfolded proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the unfolded protein response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease.

scholarly journals Loss of BOK Has a Minor Impact on Acetaminophen Overdose-Induced Liver Damage in Mice

2021 ◽  
Vol 22 (6) ◽  
pp. 3281
Author(s):  
Samara Naim ◽  
Yuniel Fernandez-Marrero ◽  
Simone de Brot ◽  
Daniel Bachmann ◽  
Thomas Kaufmann
Keyword(s):  
Liver Injury ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Western World ◽  
Liver Necrosis ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
A Minor ◽  
Protein Response ◽  
The Impact

Acetaminophen (APAP) is one of the most commonly used analgesic and anti-pyretic drugs, and APAP intoxication is one of the main reasons for liver transplantation following liver failure in the Western world. While APAP poisoning ultimately leads to liver necrosis, various programmed cell death modalities have been implicated, including ER stress-triggered apoptosis. The BCL-2 family member BOK (BCL-2-related ovarian killer) has been described to modulate the unfolded protein response and to promote chemical-induced liver injury. We therefore investigated the impact of the loss of BOK following APAP overdosing in mice. Surprisingly, we observed sex-dependent differences in the activation of the unfolded protein response (UPR) in both wildtype (WT) and Bok-/- mice, with increased activation of JNK in females compared with males. Loss of BOK led to a decrease in JNK activation and a reduced percentage of centrilobular necrosis in both sexes after APAP treatment; however, this protection was more pronounced in Bok-/- females. Nevertheless, serum ALT and AST levels of Bok-/- and WT mice were comparable, indicating that there was no major difference in the overall outcome of liver injury. We conclude that after APAP overdosing, loss of BOK affects initiating signaling steps linked to ER stress, but has a more minor impact on the outcome of liver necrosis. Furthermore, we observed sex-dependent differences that might be worthwhile to investigate.

scholarly journals RiboTag-Seq Reveals the Activation of the Unfolded Protein Response in Striatal Microglia Induced by Ethanol Withdrawal

2020 ◽  
Author(s):  
Brett D. Dufour ◽  
Kevin R. Coffey ◽  
Atom J. Lesiak ◽  
Gwenn A. Garden ◽  
John F. Neumaier
Keyword(s):  
Gene Expression ◽  
Unfolded Protein Response ◽  
Alcohol Intoxication ◽  
Ethanol Withdrawal ◽  
Differentially Expressed ◽  
Cytokine Signaling ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
The Impact

Repeated cycles of alcohol intoxication and withdrawal both induce profound changes in gene expression that can contribute to the physiological and behavioral consequences of ethanol. Since neuroinflammation is an important consequence of these changes, we used a novel strategy to investigate the impact of repeated cycles of chronic intermittent ethanol vapor and withdrawal on the RNAs actively undergoing translation in striatal microglia. RiboTag was selectively expressed in the microglia of transgenic mice and was used to immunopurify the RNA “translatome” from striatal microglia, yielding a snapshot of RNA translation during alcohol intoxication and after 8 hours of withdrawal. We obtained highly enriched microglial RNAs and analyzed these in individual animals by deep sequencing. We found a dramatic shift in gene expression during acute intoxication compared to air-exposed controls, with increases in genes and pathways associated with cytokine signaling, indicating increased neuroinflammation and microglial activation. After 8 hours of ethanol withdrawal, many inflammatory pathways remained upregulated but phagocytotic and proapoptotic pathways were increased. Using an unbiased bioinformatic method, weighted gene coexpression network analysis, multiple differentially expressed gene modules were identified. One in particular was differentially expressed in ethanol intoxicated vs. withdrawing animals, and there was a strong correlation between the centrality of the genes to this gene network and their individual statistical significance in differential expression. The unfolded protein response was over-represented in this network after withdrawal. The induction of this pathway in microglia is important since this cellular stress response can either lead towards restoration of normal function or apoptosis.

scholarly journals The Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy

Circulation ◽  
2021 ◽  
Author(s):  
Dries A.M. Feyen ◽  
Isaac Perea-Gil ◽  
Renee G.C. Maas ◽  
Magdalena Harakalova ◽  
Alexandra A. Gavidia ◽  
...  
Keyword(s):  
Single Cell ◽  
Unfolded Protein Response ◽  
Rna Sequencing ◽  
Therapeutic Potential ◽  
Compensatory Mechanism ◽  
Unfolded Protein ◽  
Single Cell Rna Sequencing ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
The Impact

Background: Phospholamban (PLN) is a critical regulator of calcium cycling and contractility in the heart. The loss of arginine at position 14 in PLN (R14del) is associated with dilated cardiomyopathy (DCM) with a high prevalence of ventricular arrhythmias. How the R14 deletion causes DCM is poorly understood and there are no disease-specific therapies. Methods: We used single-cell RNA sequencing to uncover PLN R14del disease-mechanisms in human induced pluripotent stem cells (hiPSC-CMs). We utilized both 2D and 3D functional contractility assays to evaluate the impact of modulating disease relevant pathways in PLN R14del hiPSC-CMs. Results: Modeling of the PLN R14del cardiomyopathy with isogenic pairs of hiPSC-CMs recapitulated the contractile deficit associated with the disease in vitro . Single-cell RNA sequencing revealed the induction of the unfolded protein response pathway (UPR) in PLN R14del compared to isogenic control hiPSC-CMs. The activation of UPR was also evident in the hearts from PLN R14del patients. Silencing of each of the three main UPR signaling branches (IRE1, ATF6, or PERK) by siRNA exacerbated the contractile dysfunction of PLN R14del hiPSC-CMs. We explored the therapeutic potential of activating the UPR with a small molecule activator, BiP protein Inducer X (BiX). PLN R14del hiPSC-CMs treated with BiX showed a dose-dependent amelioration of the contractility deficit of in both 2D cultures and 3D engineered heart tissues without affecting calcium homeostasis. Conclusions: Together, these findings suggest that the UPR exerts a protective effect in the setting of PLN R14del cardiomyopathy and that modulation of the UPR might be exploited therapeutically.

scholarly journals EPO and TMBIM3/GRINA Promote the Activation of the Adaptive Arm and Counteract the Terminal Arm of the Unfolded Protein Response after Murine Transient Cerebral Ischemia

2019 ◽  
Vol 20 (21) ◽  
pp. 5421 ◽  
Author(s):  
Pardes Habib ◽  
Ann-Sophie Stamm ◽  
Joerg B. Schulz ◽  
Arno Reich ◽  
Alexander Slowik ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Unfolded Protein Response ◽  
Calcium Release ◽  
Mrna Levels ◽  
Mixed Cell ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
The Impact

Ischemic stroke is known to cause the accumulation of misfolded proteins and loss of calcium homeostasis leading to impairment of endoplasmic reticulum (ER) function. The unfolded protein response (UPR) is an ER-located and cytoprotective pathway that aims to resolve ER stress. Transmembrane BAX inhibitor-1 motif-containing (TMBIM) protein family member TMBIM3/GRINA is highly expressed in the brain and mostly located at the ER membrane suppressing ER calcium release by inositol-1,4,5-trisphosphate receptors. GRINA confers neuroprotection and is regulated by erythropoietin (EPO) after murine cerebral ischemia. However, the role of GRINA and the impact of EPO treatment on the post-ischemic UPR have not been elucidated yet. We subjected GRINA-deficient (Grina−/−) and wildtype mice to transient (30 min) middle cerebral artery occlusion (tMCAo) followed by 6 h or 72 h of reperfusion. We administered EPO or saline 0, 24 and 48 h after tMCAo/sham surgery. Oxygen–glucose deprivation (OGD) and pharmacological stimulation of the UPR using Tunicamycin and Thapsigargin were carried out in primary murine cortical mixed cell cultures. Treatment with the PERK-inhibitor GSK-2606414, IRE1a-RNase-inhibitor STF-083010 and EPO was performed 1 h prior to either 1 h, 2 h or 3 h of OGD. We found earlier and larger infarct demarcations in Grina−/− mice compared to wildtype mice, which was accompanied by a worse neurological outcome and an abolishment of EPO-mediated neuroprotection after ischemic stroke. In addition, GRINA-deficiency increased apoptosis and the activation of the corresponding PERK arm of the UPR after stroke. EPO enhanced the post-ischemic activation of pro-survival IRE1a and counteracted the pro-apoptotic PERK branch of the UPR. Both EPO and the PERK-inhibitor GSK-2606414 reduced cell death and regulated Grina mRNA levels after OGD. In conclusion, GRINA plays a crucial role in post-ischemic UPR and the use of both GSK-2606414 and EPO might lead to neuroprotection.

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