scholarly journals Effect of Tff3 Deficiency and ER Stress in the Liver

2019 ◽  
Vol 20 (18) ◽  
pp. 4389
Author(s):  
Kate Šešelja ◽  
Iva Bazina ◽  
Jessica Welss ◽  
Martin Schicht ◽  
Friedrich Paulsen ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Proteins ◽  
Stress Genes ◽  
Background Strain ◽  
Unfolded Protein ◽  
Pathological Mechanism ◽  
Lipid Vacuoles ◽  
Trefoil Factor Family ◽  
Protein Response

Endoplasmic reticulum (ER) stress, a cellular condition caused by the accumulation of unfolded proteins inside the ER, has been recognized as a major pathological mechanism in a variety of conditions, including cancer, metabolic and neurodegenerative diseases. Trefoil factor family (TFFs) peptides are present in different epithelial organs, blood supply, neural tissues, as well as in the liver, and their deficiency has been linked to the ER function. Complete ablation of Tff3 expression is observed in steatosis, and as the most prominent change in the early phase of diabetes in multigenic mouse models of diabesity. To elucidate the role of Tff3 deficiency on different pathologically relevant pathways, we have developed a new congenic mouse model Tff3−/−/C57BL6/N from a mixed background strain (C57BL6/N /SV129) by using a speed congenics approach. Acute ER stress was evoked by tunicamycin treatment, and mice were sacrificed after 24 h. Afterwards the effect of Tff3 deficiency was evaluated with regard to the expression of relevant oxidative and ER stress genes, relevant proinflammatory cytokines/chemokines, and the global protein content. The most dramatic change was noticed at the level of inflammation-related genes, while markers for unfolded protein response were not significantly affected. Ultrastructural analysis confirmed that the size of lipid vacuoles was affected as well. Since the liver acts as an important metabolic and immunological organ, the influence of Tff3 deficiency and physiological function possibly reflects on the whole organism.

scholarly journals Loss of Dicer1 in mouse embryonic fibroblasts impairs ER stress-induced apoptosis

2015 ◽  
Author(s):  
Ananya Gupta ◽  
Danielle Read ◽  
Deepu Oommen ◽  
Afshin Samali ◽  
SANJEEV GUPTA
Keyword(s):  
Er Stress ◽  
Mirna Biogenesis ◽  
Unfolded Proteins ◽  
Embryonic Fibroblasts ◽  
Unfolded Protein ◽  
Critical Components ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Protein Response

The endoplasmic reticulum (ER) is the site of folding for membrane and secreted proteins. Accumulation of unfolded or misfolded proteins in the ER triggers the unfolded protein response (UPR). The UPR can promote survival by reducing the load of unfolded proteins through upregulation of chaperones and global attenuation of protein synthesis. However, when ER stress is acute or prolonged cells undergo apoptosis. In this study we sought to determine the effect of globally compromised microRNA biogenesis on the UPR and ER stress-induced apoptosis. Here we report the role of Dicer-dependent miRNA biogenesis during the UPR and ER stress-induced apoptosis. We show that ER stress-induced caspase activation and apoptosis is attenuated in Dicer deficient fibroblasts. ER stress-mediated induction of GRP78, the key ER resident chaperone, and also HERP, an important component of ER-associated degradation, are significantly increased in Dicer deficient cells. Expression of the BCL-2 family members BIM and MCL1 were significantly higher in Dicer-null fibroblasts. However, ER stress-mediated induction of pro-apoptotic BH3 only protein BIM was compromised in Dicer mutant cells.These observations demonstrate key roles for Dicer in the UPR and implicate miRNAs as critical components of UPR.

scholarly journals The Emerging Role of Electrophiles as a Key Regulator for Endoplasmic Reticulum (ER) Stress

2019 ◽  
Vol 20 (7) ◽  
pp. 1783 ◽  
Author(s):  
Takasugi ◽  
Hiraoka ◽  
Nakahara ◽  
Akiyama ◽  
Fujikawa ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Stress Sensors ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Protein Disulfide ◽  
The Relationship

The unfolded protein response (UPR) is activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which is called ER stress. ER stress sensors PERK, IRE1, and ATF6 play a central role in the initiation and regulation of the UPR; they inhibit novel protein synthesis and upregulate ER chaperones, such as protein disulfide isomerase, to remove unfolded proteins. However, when recovery from ER stress is difficult, the UPR pathway is activated to eliminate unhealthy cells. This signaling transition is the key event of many human diseases. However, the precise mechanisms are largely unknown. Intriguingly, reactive electrophilic species (RES), which exist in the environment or are produced through cellular metabolism, have been identified as a key player of this transition. In this review, we focused on the function of representative RES: nitric oxide (NO) as a gaseous RES, 4-hydroxynonenal (HNE) as a lipid RES, and methylmercury (MeHg) as an environmental organic compound RES, to outline the relationship between ER stress and RES. Modulation by RES might be a target for the development of next-generation therapy for ER stress-associated diseases.

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.

Are cachexia-associated tumors transmitTERS of ER stress?

2021 ◽  
Author(s):  
Ana Sayuri Yamagata ◽  
Paula Paccielli Freire
Keyword(s):  
Er Stress ◽  
Tumor Cells ◽  
Cancer Cachexia ◽  
Genotoxic Stress ◽  
Unfolded Protein ◽  
Response To Chemotherapy ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Associated Tumors

Cancer cachexia is associated with deficient response to chemotherapy. On the other hand, the tumors of cachectic patients remarkably express more chemokines and have higher immune infiltration. For immunogenicity, a strong induction of the unfolded protein response (UPR) is necessary. UPR followed by cell surface exposure of calreticulin on the dying tumor cell is essential for its engulfment by macrophages and dendritic cells. However, some tumor cells upon endoplasmic reticulum (ER) stress can release factors that induce ER stress to other cells, in the so-called transmissible ER stress (TERS). The cells that received TERS produce more interleukin 6 (IL-6) and chemokines and acquire resistance to subsequent ER stress, nutrient deprivation, and genotoxic stress. Since ER stress enhances the release of extracellular vesicles (EVs), we suggest they can mediate TERS. It was found that ER stressed cachexia-inducing tumor cells transmit factors that trigger ER stress in other cells. Therefore, considering the role of EVs in cancer cachexia, the release of exosomes can possibly play a role in the process of blunting the immunogenicity of the cachexia-associated tumors. We propose that TERS can cause an inflammatory and immunosuppressive phenotype in cachexia-inducing tumors.

scholarly journals The Role of the ER-Induced UPR Pathway and the Efficacy of Its Inhibitors and Inducers in the Inhibition of Tumor Progression

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Anna Walczak ◽  
Kinga Gradzik ◽  
Jacek Kabzinski ◽  
Karolina Przybylowska-Sygut ◽  
Ireneusz Majsterek
Keyword(s):  
Er Stress ◽  
Molecular Mechanisms ◽  
Unfolded Proteins ◽  
Cell Protection ◽  
Protection Mechanism ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
A Cell ◽  
The Unfolded Protein Response ◽  
Protein Response

Cancer is the second most frequent cause of death worldwide. It is considered to be one of the most dangerous diseases, and there is still no effective treatment for many types of cancer. Since cancerous cells have a high proliferation rate, it is pivotal for their proper functioning to have the well-functioning protein machinery. Correct protein processing and folding are crucial to maintain tumor homeostasis. Endoplasmic reticulum (ER) stress is one of the leading factors that cause disturbances in these processes. It is induced by impaired function of the ER and accumulation of unfolded proteins. Induction of ER stress affects many molecular pathways that cause the unfolded protein response (UPR). This is the way in which cells can adapt to the new conditions, but when ER stress cannot be resolved, the UPR induces cell death. The molecular mechanisms of this double-edged sword process are involved in the transition of the UPR either in a cell protection mechanism or in apoptosis. However, this process remains poorly understood but seems to be crucial in the treatment of many diseases that are related to ER stress. Hence, understanding the ER stress response, especially in the aspect of pathological consequences of UPR, has the potential to allow us to develop novel therapies and new diagnostic and prognostic markers for cancer.

scholarly journals Activation of Mammalian Unfolded Protein Response Is Compatible with the Quality Control System Operating in the Endoplasmic Reticulum

2004 ◽  
Vol 15 (6) ◽  
pp. 2537-2548 ◽  
Author(s):  
Satomi Nadanaka ◽  
Hiderou Yoshida ◽  
Fumi Kano ◽  
Masayuki Murata ◽  
Kazutoshi Mori
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Control System ◽  
Golgi Apparatus ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Protein Response

Newly synthesized secretory and transmembrane proteins are folded and assembled in the endoplasmic reticulum (ER) where an efficient quality control system operates so that only correctly folded molecules are allowed to move along the secretory pathway. The productive folding process in the ER has been thought to be supported by the unfolded protein response (UPR), which is activated by the accumulation of unfolded proteins in the ER. However, a dilemma has emerged; activation of ATF6, a key regulator of mammalian UPR, requires intracellular transport from the ER to the Golgi apparatus. This suggests that unfolded proteins might be leaked from the ER together with ATF6 in response to ER stress, exhibiting proteotoxicity in the secretory pathway. We show here that ATF6 and correctly folded proteins are transported to the Golgi apparatus via the same route and by the same mechanism under conditions of ER stress, whereas unfolded proteins are retained in the ER. Thus, activation of the UPR is compatible with the quality control in the ER and the ER possesses a remarkable ability to select proteins to be transported in mammalian cells in marked contrast to yeast cells, which actively utilize intracellular traffic to deal with unfolded proteins accumulated in the ER.

scholarly journals De-silencing Grb10 contributes to acute ER stress-induced steatosis in mouse liver

2018 ◽  
Vol 60 (4) ◽  
pp. 285-297 ◽  
Author(s):  
Liping Luo ◽  
Wanxiang Jiang ◽  
Hui Liu ◽  
Jicheng Bu ◽  
Ping Tang ◽  
...  
Keyword(s):  
Er Stress ◽  
Mouse Liver ◽  
Fetal Liver ◽  
Growth Factor Receptor ◽  
Negative Regulator ◽  
Unfolded Protein ◽  
Adult Mice ◽  
Mtorc1 Signaling ◽  
Protein Response

The growth factor receptor bound protein GRB10 is an imprinted gene product and a key negative regulator of the insulin, IGF1 and mTORC1 signaling pathways. GRB10 is highly expressed in mouse fetal liver but almost completely silenced in adult mice, suggesting a potential detrimental role of this protein in adult liver function. Here we show that the Grb10 gene could be reactivated in adult mouse liver by acute endoplasmic reticulum stress (ER stress) such as tunicamycin or a short-term high-fat diet (HFD) challenge, concurrently with increased unfolded protein response (UPR) and hepatosteatosis. Lipogenic gene expression and acute ER stress-induced hepatosteatosis were significantly suppressed in the liver of the liver-specific GRB10 knockout mice, uncovering a key role of Grb10 reactivation in acute ER stress-induced hepatic lipid dysregulation. Mechanically, acute ER stress induces Grb10 reactivation via an ATF4-mediated increase in Grb10 gene transcription. Our study demonstrates for the first time that the silenced Grb10 gene can be reactivated by acute ER stress and its reactivation plays an important role in the early development of hepatic steatosis.

scholarly journals The unfolded protein response in relation to mitochondrial biogenesis in skeletal muscle cells

2017 ◽  
Vol 312 (5) ◽  
pp. C583-C594 ◽  
Author(s):  
Zahra S. Mesbah Moosavi ◽  
David A. Hood
Keyword(s):  
Er Stress ◽  
Mitochondrial Biogenesis ◽  
Contractile Activity ◽  
Muscle Cells ◽  
Unfolded Proteins ◽  
Protein Levels ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Mitochondrial Adaptations

Mitochondria comprise both nuclear and mitochondrially encoded proteins requiring precise stoichiometry for their integration into functional complexes. The augmented protein synthesis associated with mitochondrial biogenesis results in the accumulation of unfolded proteins, thus triggering cellular stress. As such, the unfolded protein responses emanating from the endoplasmic reticulum (UPRER) or the mitochondrion (UPRMT) are triggered to ensure correct protein handling. Whether this response is necessary for mitochondrial adaptations is unknown. Two models of mitochondrial biogenesis were used: muscle differentiation and chronic contractile activity (CCA) in murine muscle cells. After 4 days of differentiation, our findings depict selective activation of the UPRMTin which chaperones decreased; however, Sirt3 and UPRERmarkers were elevated. To delineate the role of ER stress in mitochondrial adaptations, the ER stress inhibitor TUDCA was administered. Surprisingly, mitochondrial markers COX-I, COX-IV, and PGC-1α protein levels were augmented up to 1.5-fold above that of vehicle-treated cells. Similar results were obtained in myotubes undergoing CCA, in which biogenesis was enhanced by ~2–3-fold, along with elevated UPRMTmarkers Sirt3 and CPN10. To verify whether the findings were attributable to the terminal UPRERbranch directed by the transcription factor CHOP, cells were transfected with CHOP siRNA. Basally, COX-I levels increased (~20%) and COX-IV decreased (~30%), suggesting that CHOP influences mitochondrial composition. This effect was fully restored by CCA. Therefore, our results suggest that mitochondrial biogenesis is independent of the terminal UPRER. Under basal conditions, CHOP is required for the maintenance of mitochondrial composition, but not for differentiation- or CCA-induced mitochondrial biogenesis.

scholarly journals Effects of Jasmonic Acid in ER Stress and Unfolded Protein Response in Tomato Plants

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1031
Author(s):  
Zalán Czékus ◽  
Orsolya Csíkos ◽  
Attila Ördög ◽  
Irma Tari ◽  
Péter Poór
Keyword(s):  
Jasmonic Acid ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Transcript Accumulation ◽  
Chemical Chaperone ◽  
Tomato Plants ◽  
Transcript Levels ◽  
Unfolded Protein ◽  
Protein Response

Endoplasmic reticulum (ER) stress elicits a protective mechanism called unfolded protein response (UPR) to maintain cellular homeostasis, which can be regulated by defence hormones. In this study, the physiological role of jasmonic acid (JA) in ER stress and UPR signalling has been investigated in intact leaves of tomato plants. Exogenous JA treatments not only induced the transcript accumulation of UPR marker gene SlBiP but also elevated transcript levels of SlIRE1 and SlbZIP60. By the application of JA signalling mutant jai1 plants, the role of JA in ER stress sensing and signalling was further investigated. Treatment with tunicamycin (Tm), the inhibitor of N-glycosylation of secreted glycoproteins, increased the transcript levels of SlBiP. Interestingly, SlIRE1a and SlIRE1b were significantly lower in jai1. In contrast, the transcript accumulation of Bax Inhibitor-1 (SlBI1) and SlbZIP60 was higher in jai1. To evaluate how a chemical chaperone modulates Tm-induced ER stress, plants were treated with sodium 4-phenylbutyrate, which also decreased the Tm-induced increase in SlBiP, SlIRE1a, and SlBI1 transcripts. In addition, it was found that changes in hydrogen peroxide content, proteasomal activity, and lipid peroxidation induced by Tm is regulated by JA, while nitric oxide was not involved in ER stress and UPR signalling in leaves of tomato.

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