scholarly journals Unfolded protein response triggers differential apoptotic mechanisms in ovaries and early embryos exposed to maternal type 1 diabetes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Aslı Okan ◽  
Necdet Demir ◽  
Berna Sozen
Keyword(s):  
Embryonic Development ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Molecular Mechanisms ◽  
Early Embryonic Development ◽  
Unfolded Protein ◽  
Caspase 12 ◽  
Early Embryos ◽  
Protein Response

AbstractDiabetes mellitus (DM) has profound effects on the female mammalian reproductive system, and early embryonic development, reducing female reproductive outcomes and inducing developmental programming in utero. However, the underlying cellular and molecular mechanisms remain poorly defined. Accumulating evidence implicates endoplasmic reticulum (ER)-stress with maternal DM associated pathophysiology. Yet the direct pathologies and causal events leading to ovarian dysfunction and altered early embryonic development have not been determined. Here, using an in vivo mouse model of Type 1 DM and in vitro hyperglycaemia-exposure, we demonstrate the activation of ER-stress within adult ovarian tissue and pre-implantation embryos. In diabetic ovaries, we show that the unfolded protein response (UPR) triggers an apoptotic cascade by the co-activation of Caspase 12 and Cleaved Caspase 3 transducers. Whereas DM-exposed early embryos display differential ER-associated responses; by activating Chop in within embryonic precursors and Caspase 12 within placental precursors. Our results offer new insights for understanding the pathological effects of DM on mammalian ovarian function and early embryo development, providing new evidence of its mechanistic link with ER-stress in mice.

scholarly journals A Mouse Model Suggests Two Mechanisms for Thyroid Alterations in Infantile Cystinosis: Decreased Thyroglobulin Synthesis Due to Endoplasmic Reticulum Stress/Unfolded Protein Response and Impaired Lysosomal Processing

Endocrinology ◽  
2015 ◽  
Vol 156 (6) ◽  
pp. 2349-2364 ◽  
Author(s):  
H. P. Gaide Chevronnay ◽  
V. Janssens ◽  
P. Van Der Smissen ◽  
X. H. Liao ◽  
Y. Abid ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Molecular Mechanisms ◽  
Primary Hypothyroidism ◽  
Overt Hypothyroidism ◽  
Nephropathic Cystinosis ◽  
Unfolded Protein ◽  
Activating Transcription Factor 4 ◽  
Protein Response

Abstract Thyroid hormones are released from thyroglobulin (Tg) in lysosomes, which are impaired in infantile/nephropathic cystinosis. Cystinosis is a lysosomal cystine storage disease due to defective cystine exporter, cystinosin. Cystinotic children develop subclinical and then overt hypothyroidism. Why hypothyroidism is the most frequent and earliest endocrine complication of cystinosis is unknown. We here defined early alterations in Ctns−/− mice thyroid and identified subcellular and molecular mechanisms. At 9 months, T4 and T3 plasma levels were normal and TSH was moderately increased (∼4-fold). By histology, hyperplasia and hypertrophy of most follicles preceded colloid exhaustion. Increased immunolabeling for thyrocyte proliferation and apoptotic shedding indicated accelerated cell turnover. Electron microscopy revealed endoplasmic reticulum (ER) dilation, apical lamellipodia indicating macropinocytic colloid uptake, and lysosomal cystine crystals. Tg accumulation in dilated ER contrasted with mRNA down-regulation. Increased expression of ER chaperones, glucose-regulated protein of 78 kDa and protein disulfide isomerase, associated with alternative X-box binding protein-1 splicing, revealed unfolded protein response (UPR) activation by ER stress. Decreased Tg mRNA and ER stress suggested reduced Tg synthesis. Coordinated increase of UPR markers, activating transcription factor-4 and C/EBP homologous protein, linked ER stress to apoptosis. Hormonogenic cathepsins were not altered, but lysosome-associated membrane protein-1 immunolabeling disclosed enlarged vesicles containing iodo-Tg and impaired lysosomal fusion. Isopycnic fractionation showed iodo-Tg accumulation in denser lysosomes, suggesting defective lysosomal processing and hormone release. In conclusion, Ctns−/− mice showed the following alterations: 1) compensated primary hypothyroidism and accelerated thyrocyte turnover; 2) impaired Tg production linked to ER stress/UPR response; and 3) altered endolysosomal trafficking and iodo-Tg processing. The Ctns−/− thyroid is useful to study disease progression and evaluate novel therapies.

scholarly journals Coxsackievirus B3 Infection Activates the Unfolded Protein Response and Induces Apoptosis through Downregulation of p58IPK and Activation of CHOP and SREBP1

2010 ◽  
Vol 84 (17) ◽  
pp. 8446-8459 ◽  
Author(s):  
Huifang M. Zhang ◽  
Xin Ye ◽  
Yue Su ◽  
Ji Yuan ◽  
Zhen Liu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Hela Cells ◽  
Coxsackievirus B3 ◽  
Unfolded Protein ◽  
Caspase 12 ◽  
Cvb3 Infection ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT Cardiomyocyte apoptosis is a hallmark of coxsackievirus B3 (CVB3)-induced myocarditis. We used cardiomyocytes and HeLa cells to explore the cellular response to CVB3 infection, with a focus on pathways leading to apoptosis. CVB3 infection triggered endoplasmic reticulum (ER) stress and differentially regulated the three arms of the unfolded protein response (UPR) initiated by the proximal ER stress sensors ATF6a (activating transcription factor 6a), IRE1-XBP1 (X box binding protein 1), and PERK (PKR-like ER protein kinase). Upon CVB3 infection, glucose-regulated protein 78 expression was upregulated, and in turn ATF6a and XBP1 were activated via protein cleavage and mRNA splicing, respectively. UPR activity was further confirmed by the enhanced expression of UPR target genes ERdj4 and EDEM1. Surprisingly, another UPR-associated gene, p58IPK, which often is upregulated during infections with other types of viruses, was downregulated at both mRNA and protein levels after CVB3 infection. These findings were observed similarly for uninfected Tet-On HeLa cells induced to overexpress ATF6a or XBP1. In exploring potential connections between the three UPR pathways, we found that the ATF6a-induced downregulation of p58IPK was associated with the activation of PKR (PERK) and the phosphorylation of eIF2α, suggesting that p58IPK, a negative regulator of PERK and PKR, mediates cross-talk between the ATF6a/IRE1-XBP1 and PERK arms. Finally, we found that CVB3 infection eventually produced the induction of the proapoptoic transcription factor CHOP and the activation of SREBP1 and caspase-12. Taken together, these data suggest that CVB3 infection activates UPR pathways and induces ER stress-mediated apoptosis through the suppression of P58IPK and induction/activation of CHOP, SREBP1, and caspase-12.

scholarly journals Downregulation of miR-17-92 cluster by PERK fine-tunes unfolded protein response mediated apoptosis

2020 ◽  
Author(s):  
Danielle E. Read ◽  
Ananya Gupta ◽  
Karen Cawley ◽  
Laura Fontana ◽  
Patrizia Agostinis ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
Proximal Region ◽  
Dependent Manner ◽  
Unfolded Protein ◽  
Promoter Deletion Analysis ◽  
Protein Response

AbstractAn important event in the unfolded protein response (UPR) is the activation of the endoplasmic reticulum kinase PERK (EIF2AK3). The PERK signalling branch first mediates a prosurvival response, which switches into a proapoptotic response upon prolonged ER stress. However, the molecular mechanisms of PERK-mediated cell death are not well understood. Here we show that expression of the primary miR-17-92 transcript and mature miRNAs belonging to miR-17-92 cluster is decreased during UPR. We found that activity of miR-17-92 promoter reporter was reduced during UPR in a PERK-dependent manner. We show that activity of miR-17-92 promoter is repressed by ectopic expression of ATF4 and NRF2. The promoter deletion analysis and ChIP assays mapped the region responding to UPR-mediated repression to site in the proximal region of the miR-17-92 promoter. Hypericin-mediated photo-oxidative ER damage reduced the expression of miRNAs belonging to miR-17-92 cluster in wild-type but not in PERK-deficient cells. Importantly, ER stress-induced apoptosis was inhibited upon miR-17-92 overexpression in SH-SY5Y and H9c2 cells. Our results reveal a novel function for NRF2, where repression of miR-17-92 cluster by NRF2 plays an important role in ER stress-mediated apoptosis. The data presented here provides mechanistic details how sustained PERK signalling via NRF2 mediated repression of miR-17-92 cluster can potentiate cell death.

scholarly journals Downregulation of miR-17-92 Cluster by PERK Fine-Tunes Unfolded Protein Response Mediated Apoptosis

Life ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 30
Author(s):  
Danielle E. Read ◽  
Ananya Gupta ◽  
Karen Cawley ◽  
Laura Fontana ◽  
Patrizia Agostinis ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
Proximal Region ◽  
Dependent Manner ◽  
Unfolded Protein ◽  
Promoter Deletion Analysis ◽  
Protein Response

An important event in the unfolded protein response (UPR) is activation of the endoplasmic reticulum (ER) kinase PERK. The PERK signalling branch initially mediates a prosurvival response, which progresses to a proapoptotic response upon prolonged ER stress. However, the molecular mechanisms of PERK-mediated cell death are not well understood. Here we show that expression of the primary miR-17-92 transcript and mature miRNAs belonging to the miR-17-92 cluster are decreased during UPR. We found that miR-17-92 promoter reporter activity was reduced during UPR in a PERK-dependent manner. Furthermore, we show that activity of the miR-17-92 promoter is repressed by ectopic expression of ATF4 and NRF2. Promoter deletion analysis mapped the region responding to UPR-mediated repression to a site in the proximal region of the miR-17-92 promoter. Hypericin-mediated photo-oxidative ER damage reduced the expression of miRNAs belonging to the miR-17-92 cluster in wild-type but not in PERK-deficient cells. Importantly, ER stress-induced apoptosis was inhibited upon miR-17-92 overexpression in SH-SY5Y and H9c2 cells. Our results reveal a novel function for ATF4 and NRF2, where repression of the miR-17-92 cluster plays an important role in ER stress-mediated apoptosis. Mechanistic details are provided for the potentiation of cell death via sustained PERK signalling mediated repression of the miR-17-92 cluster.

scholarly journals Regulation of unfolded protein response modulator XBP1s by acetylation and deacetylation

2010 ◽  
Vol 433 (1) ◽  
pp. 245-252 ◽  
Author(s):  
Feng-Ming Wang ◽  
Yi-Jiun Chen ◽  
Hong-Jiao Ouyang
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Sirtuin 1 ◽  
Luciferase Reporter ◽  
Unfolded Protein ◽  
Wide Range ◽  
Protein Response

XBP1 (X-box-binding protein 1) is a key modulator of the UPR (unfolded protein response), which is involved in a wide range of pathological and physiological processes. The mRNA encoding the active spliced form of XBP1 (XBP1s) is generated from the unspliced form by IRE1 (inositol-requiring enzyme 1) during the UPR. However, the post-translational modulation of XBP1s remains largely unknown. In the present study, we demonstrate that XBP1s is a target of acetylation and deacetylation mediated by p300 and SIRT1 (sirtuin 1) respectively. p300 increases the acetylation and protein stability of XBP1s, and enhances its transcriptional activity, whereas SIRT1 deacetylates XBP1s and inhibits its transcriptional activity. Deficiency of SIRT1 enhances XBP1s-mediated luciferase reporter activity in HEK (human embryonic kidney)-293 cells and the up-regulation of XBP1s target gene expression under ER (endoplasmic reticulum) stress in MEFs (mouse embryonic fibroblasts). Consistent with XBP1s favouring cell survival under ER stress, Sirt1−/− MEFs display a greater resistance to ER-stress-induced apoptotic cell death compared with Sirt1+/+ MEFs. Taken together, these results suggest that acetylation/deacetylation constitutes an important post-translational mechanism in controlling protein levels, as well as the transcriptional activity, of XBP1s. The present study provides a novel insight into the molecular mechanisms by which SIRT1 regulates UPR signalling.

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.

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