A Concise Review on the Role of Endoplasmic Reticulum Stress in the Development of Autoimmunity in Vitiligo Pathogenesis

Vitiligo is characterized by circumscribed depigmented macules in the skin resulting due to the autoimmune destruction of melanocytes from the epidermis. Both humoral as well as cell-mediated autoimmune responses are involved in melanocyte destruction. Several studies including ours have established that oxidative stress is involved in vitiligo onset, while autoimmunity contributes to the disease progression. However, the underlying mechanism involved in programing the onset and progression of the disease remains a conundrum. Based on several direct and indirect evidences, we suggested that endoplasmic reticulum (ER) stress might act as a connecting link between oxidative stress and autoimmunity in vitiligo pathogenesis. Oxidative stress disrupts cellular redox potential that extends to the ER causing the accumulation of misfolded proteins, which activates the unfolded protein response (UPR). The primary aim of UPR is to resolve the stress and restore cellular homeostasis for cell survival. Growing evidences suggest a vital role of UPR in immune regulation. Moreover, defective UPR has been implicated in the development of autoimmunity in several autoimmune disorders. ER stress-activated UPR plays an essential role in the regulation and maintenance of innate as well as adaptive immunity, and a defective UPR may result in systemic/tissue level/organ-specific autoimmunity. This review emphasizes on understanding the role of ER stress-induced UPR in the development of systemic and tissue level autoimmunity in vitiligo pathogenesis and its therapeutics.

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c-Jun Inhibits Thapsigargin-Induced ER Stress Through Up-Regulation of DSCR1/Adapt78

Experimental Biology and Medicine ◽

10.3181/0803-rm-84 ◽

2008 ◽

Vol 233 (10) ◽

pp. 1289-1300 ◽

Cited By ~ 25

Author(s):

Peng Zhao ◽

Xiaoyan Xiao ◽

Agnes S. Kim ◽

M. Fatima Leite ◽

Jinxia Xu ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Wild Type Mouse ◽

Mouse Fibroblast ◽

Expression Levels ◽

Mouse Fibroblasts ◽

The Unfolded Protein Response ◽

Calcineurin Activity

The endoplasmic reticulum (ER) is exquisitely sensitive to changes in its internal environment. Various conditions, collectively termed “ER stress”, can perturb ER function, leading to the activation of a complex response known as the unfolded protein response (UPR). Although c-Jun N-terminal kinase (JNK) activation is nearly always associated with cell death by various stimuli, the functional role of JNK in ER stress-induced cell death remains unclear. JNK regulates gene expression through the phosphorylation and activation of transcription factors, such as c-Jun. Here, we investigated the role of c-Jun in the regulation of ER stress-related genes. c-Jun expression levels determined the response of mouse fibroblasts to ER stress induced by thapsigargin (TG, an inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase). c-jun−/− mouse fibroblast cells were more sensitive to TG-induced cell death compared to wild-type mouse fibroblasts, while reconstitution of c-Jun expression in c-jun−/− cells (c-Jun Re) enhanced resistance to TG-induced cell death. The expression levels of ER chaperones Grp78 and Gadd153 induced by TG were lower in c-Jun Re than in c-jun−/− cells. Moreover, TG treatment significantly increased calcineurin activity in c-jun−/− cells, but not in c-Jun Re cells. In c-Jun Re cells, TG induced the expression of Adapt78, also known as the Down syndrome critical region 1 (DSCR1), which is known to block calcineurin activity. Taken together, our findings suggest that c-Jun, a transcription factor downstream of the JNK signaling pathway, up-regulates Adapt78 expression in response to TG-induced ER stress and contributes to protection against TG-induced cell death.

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Abstract 357: Hepatic ERK2 Suppresses Endoplasmic Reticulum Stress, Leading to Protection from Oxidative Stress and Endothelial Dysfunction

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.33.suppl_1.a357 ◽

2013 ◽

Vol 33 (suppl_1) ◽

Author(s):

Takehiko Kujiraoka ◽

Yasushi Satoh ◽

Makoto Ayaori ◽

Yasunaga Shiraishi ◽

Yuko Arai-Nakaya ◽

...

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Endoplasmic Reticulum ◽

Fatty Acid ◽

Endothelial Dysfunction ◽

Er Stress ◽

Vascular Complications ◽

Metabolic Remodeling ◽

And Oxidative Stress

Background Insulin signaling comprises 2 major cascades, the IRS/PI3K/Akt and Ras/Raf/MEK/ERK pathways. Many studies on the tissue-specific effects of the former pathway had been conducted, however, the role of the latter cascade in tissue-specific insulin resistance had not been investigated. High glucose/fatty acid toxicity, inflammation and oxidative stress, all of which are associated with insulin resistance, can activate ERK. Liver plays a central role of metabolism and hepatosteatosis (HST) is associated with vascular diseases. The aim of this study is to elucidate the role of hepatic ERK2 in HST, metabolic remodeling and endothelial dysfunction. Methods Serum biomarkers of vascular complications in human were compared between subjects with and without HST diagnosed by echography for regular medical checkup. Next, we created liver-specific ERK2 knockout mice (LE2KO) and fed them with a high-fat/high-sucrose diet (HFHSD) for 20 weeks. The histological analysis, the expression of hepatic sarco/endoplasmic reticulum (ER) Ca 2+ -ATPase 2 (SERCA2) and glucose-tolerance/insulin-sensitivity (GT/IS) were tested. Vascular superoxide production and endothelial function were evaluated with dihydroethidium staining and isometric tension measurement of aorta. Results The presence of HST significantly increased HOMA-IR, an indicator of insulin resistance or atherosclerotic index in human. HFHSD-fed LE2KO revealed a marked exacerbation in HST and metabolic remodeling represented by the impairment of GT/IS, elevated serum free fatty acid and hyperhomocysteinemia without changes in body weight, blood pressure and serum cholesterol/triglyceride levels. In the HFHSD-fed LE2KO, mRNA and protein expressions of hepatic SERCA2 were significantly decreased, which resulted in hepatic ER stress. Induction of vascular superoxide production and remarkable endothelial dysfunction were also observed in them. Conclusions Hepatic ERK2 revealed the suppression of hepatic ER stress and HST in vivo , which resulted in protection from vascular oxidative stress and endothelial dysfunction. HST with hepatic ER stress can be a prominent risk of vascular complications by metabolic remodeling and oxidative stress in obese-related diseases.

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The Role of Endoplasmic Reticulum Stress in Cardiovascular Disease and Exercise

International Journal of Vascular Medicine ◽

10.1155/2017/2049217 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 22

Author(s):

Junyoung Hong ◽

Kwangchan Kim ◽

Jong-Hee Kim ◽

Yoonjung Park

Keyword(s):

Cardiovascular Disease ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Signaling Pathways ◽

Protein Misfolding ◽

Unfolded Protein ◽

Activating Transcription Factor ◽

Apoptosis And Inflammation ◽

The Unfolded Protein Response

Endoplasmic reticulum (ER) stress, which is highly associated with cardiovascular disease, is triggered by a disturbance in ER function because of protein misfolding or an increase in protein secretion. Prolonged disruption of ER causes ER stress and activation of the unfolded protein response (UPR) and leads to various diseases. Eukaryotic cells respond to ER stress via three major sensors that are bound to the ER membrane: activating transcription factor 6 (ATF6), inositol-requiring protein 1α (IRE1α), and protein kinase RNA-like ER kinase (PERK). Chronic activation of ER stress causes damage in endothelial cells (EC) via apoptosis, inflammation, and oxidative stress signaling pathways. The alleviation of ER stress has recently been accepted as a potential therapeutic target to treat cardiovascular diseases such as heart failure, hypertension, and atherosclerosis. Exercise training is an effective nonpharmacological approach for preventing and alleviating cardiovascular disease. We here review the recent viewing of ER stress-mediated apoptosis and inflammation signaling pathways in cardiovascular disease and the role of exercise in ER stress-associated diseases.

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Improvement of chemotherapeutic drug efficacy by endoplasmic reticulum stress

Endocrine Related Cancer ◽

10.1530/erc-15-0019 ◽

2015 ◽

Vol 22 (2) ◽

pp. 229-238 ◽

Cited By ~ 22

Author(s):

Chrysovalantou Mihailidou ◽

Ioulia Chatzistamou ◽

Athanasios G Papavassiliou ◽

Hippokratis Kiaris

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Human Cancer ◽

Drug Efficacy ◽

Underlying Mechanism ◽

Protein Glycosylation ◽

Acute Administration ◽

Lung Cancers ◽

Human Cancer Cells ◽

The Unfolded Protein Response

Tunicamycin (TUN), an inhibitor of protein glycosylation and therefore a potent stimulator of endoplasmic reticulum (ER) stress, has been used to improve anticancer drug efficacy, but the underlying mechanism remains obscure. In this study, we show that acute administration of TUN in mice induces the unfolded protein response and suppresses the levels of P21, a cell cycle regulator with anti-apoptotic activity. The inhibition of P21 after ER stress appears to be C/EBP homologous protein (CHOP)-dependent because in CHOP-deficient mice, TUN not only failed to suppress, but rather induced the expression of P21. Results of promoter-activity reporter assays using human cancer cells and mouse fibroblasts indicated that the regulation of P21 by CHOP operates at the level of transcription and involves direct binding of CHOP transcription factor to the P21 promoter. The results of cell viability and clonogenic assays indicate that ER-stress-related suppression of P21 expression potentiates caspase activation and sensitizes cells to doxorubicin treatment, while administration of TUN to mice increases the therapeutic efficacy of anticancer therapy for HepG2 liver and A549 lung cancers.

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Rhabdomyolysis induced AKI via the regulation of endoplasmic reticulum stress and oxidative stress in PTECs

RSC Advances ◽

10.1039/c6ra18865f ◽

2016 ◽

Vol 6 (111) ◽

pp. 109639-109648 ◽

Cited By ~ 6

Author(s):

Yuying Feng ◽

Liang Ma ◽

Linfeng Liu ◽

Hyokyoung Grace Hong ◽

Xuemei Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Er Stress ◽

And Oxidative Stress ◽

Stress Activation

Mechanism for the role of ER stress and oxidative stress activation in rhabdomyolysis-associated AKI.

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Endoplasmic reticulum chaperone BiP/GRP78 knockdown leads to autophagy and cell death of arginine vasopressin neurons in mice

Scientific Reports ◽

10.1038/s41598-020-76839-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Yohei Kawaguchi ◽

Daisuke Hagiwara ◽

Takashi Miyata ◽

Yuichi Hodai ◽

Junki Kurimoto ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Arginine Vasopressin ◽

Urine Volume ◽

Neuronal Loss ◽

Protective Role ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Vasopressin Neurons

AbstractThe immunoglobulin heavy chain binding protein (BiP), also referred to as 78-kDa glucose-regulated protein (GRP78), is a pivotal endoplasmic reticulum (ER) chaperone which modulates the unfolded protein response under ER stress. Our previous studies showed that BiP is expressed in arginine vasopressin (AVP) neurons under non-stress conditions and that BiP expression is upregulated in proportion to the increased AVP expression under dehydration. To clarify the role of BiP in AVP neurons, we used a viral approach in combination with shRNA interference for BiP knockdown in mouse AVP neurons. Injection of a recombinant adeno-associated virus equipped with a mouse AVP promoter and BiP shRNA cassette provided specific BiP knockdown in AVP neurons of the supraoptic (SON) and paraventricular nuclei (PVN) in mice. AVP neuron-specific BiP knockdown led to ER stress and AVP neuronal loss in the SON and PVN, resulting in increased urine volume due to lack of AVP secretion. Immunoelectron microscopy of AVP neurons revealed that autophagy was activated through the process of AVP neuronal loss, whereas no obvious features characteristic of apoptosis were observed. Pharmacological inhibition of autophagy by chloroquine exacerbated the AVP neuronal loss due to BiP knockdown, indicating a protective role of autophagy in AVP neurons under ER stress. In summary, our results demonstrate that BiP is essential for the AVP neuron system.

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Salicylic acid-independent role of NPR1 is required for protection from proteotoxic stress in the plant endoplasmic reticulum

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1802254115 ◽

2018 ◽

Vol 115 (22) ◽

pp. E5203-E5212 ◽

Cited By ~ 19

Author(s):

Ya-Shiuan Lai ◽

Luciana Renna ◽

John Yarema ◽

Cristina Ruberti ◽

Sheng Yang He ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Salicylic Acid ◽

Er Stress ◽

Stress Responses ◽

Unfolded Protein ◽

Redox Activation ◽

Genetic Level ◽

The Unfolded Protein Response ◽

Protein Response

The unfolded protein response (UPR) is an ancient signaling pathway designed to protect cells from the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER). Because misregulation of the UPR is potentially lethal, a stringent surveillance signaling system must be in place to modulate the UPR. The major signaling arms of the plant UPR have been discovered and rely on the transcriptional activity of the transcription factors bZIP60 and bZIP28 and on the kinase and ribonuclease activity of IRE1, which splices mRNA to activate bZIP60. Both bZIP28 and bZIP60 modulate UPR gene expression to overcome ER stress. In this study, we demonstrate at a genetic level that the transcriptional role of bZIP28 and bZIP60 in ER-stress responses is antagonized by nonexpressor of PR1 genes 1 (NPR1), a critical redox-regulated master regulator of salicylic acid (SA)-dependent responses to pathogens, independently of its role in SA defense. We also establish that the function of NPR1 in the UPR is concomitant with ER stress-induced reduction of the cytosol and translocation of NPR1 to the nucleus where it interacts with bZIP28 and bZIP60. Our results support a cellular role for NPR1 as well as a model for plant UPR regulation whereby SA-independent ER stress-induced redox activation of NPR1 suppresses the transcriptional role of bZIP28 and bZIP60 in the UPR.

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Zinc-dependent changes in oxidative and endoplasmic reticulum stress during cardiomyocyte hypoxia/reoxygenation

Biological Chemistry ◽

10.1515/hsz-2020-0167 ◽

2020 ◽

Vol 401 (11) ◽

pp. 1257-1271

Author(s):

Vijaya Lakshmi Bodiga ◽

Praveen Kumar Vemuri ◽

Greeshma Nimmagadda ◽

Sreedhar Bodiga

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Cell Survival ◽

Caspase 3 ◽

Zinc Homeostasis ◽

Intracellular Zinc ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Hypoxia Reoxygenation

AbstractMyocardial zinc dyshomeostasis is associated with caspase-3 activation, ErbB2 degradation and apoptosis during hypoxia/reoxygenation. Zinc pyrithione replenishes intracellular zinc, suppresses caspase-3, augments ErbB2 levels and improves cell survival. We hypothesize that zinc is capable of modulating redox and endoplasmic reticulum (ER) stress in the setting of cardiomyocyte hypoxia-reoxygenation. Hypoxia/reoxygenation lowered intracellular zinc, increased ER as well as oxidative stress in H9c2 cells, both of which were effectively attenuated by zinc supplementation. Silencing of gp91phox attenuated oxidative and ER stress, decreased caspase-3 activation and improved cell survival. Mimicking the oxidative insult using 50 μM H2O2 increased the caspase-3 activity that correlated with decreased ErbB2 levels, concomitant with augmented ER stress. N-acetyl cysteine (NAC) administration completely suppressed ER stress as well as caspase-3 activity. Zinc depletion using TPEN also resulted in lowered ErbB2 and increased apoptosis, along with NOX2 mRNA upregulation, increased oxidative and ER stress. Repletion with zinc suppressed NOX2 mRNA, lowered oxidative as well as ER stress and decreased cell death. These results suggest that zinc dyshomeostasis, along with oxidative stress contribute to the unfolded protein response during myocardial H/R and that zinc replenishment corrects zinc homeostasis, alleviates associated stress and improves cardiomyocyte survival.

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Echinacoside Upregulates Sirt1 to Suppress Endoplasmic Reticulum Stress and Inhibit Extracellular Matrix Degradation In Vitro and Ameliorates Osteoarthritis In Vivo

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/3137066 ◽

2021 ◽

Vol 2021 ◽

pp. 1-21

Author(s):

Zhen Lin ◽

Cheng Teng ◽

Libin Ni ◽

Zhao Zhang ◽

Xinlei Lu ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Underlying Mechanism ◽

Cellular Damage ◽

Cellular Effects ◽

Tert Butyl Hydroperoxide ◽

Ecm Degradation

Background. Osteoarthritis (OA) is a progressive illness that destroys cartilage. Oxidative stress is a major contributor of OA, while endoplasmic reticulum (ER) stress is the key cellular damage under oxidative stress in chondrocytes. Echinacoside (ECH) is the main extract and active substance of Cistanche, with potent antioxidative stress (OS) properties, and currently under clinical trials in China. However, its function in OA is yet to be determined. Purpose. We aimed to explore the specific role of ECH in the occurrence and development of OA and its underlying mechanism in vivo and in vitro. Methods. After the mice were anesthetized, the bilateral medial knee joint meniscus resection was performed to establish the DMM model. TBHP was used to induce oxidative stress to establish the OA model in chondrocytes in vitro. Western blot and RT-PCR were used to evaluate the level of ER stress-related biomarkers such as p-PERK/PERK, GRP78, ATF4, p-eIF2α/eIF2α, and CHOP and apoptosis-related proteins such as BAX, Bcl-2, and cleaved caspase-3. Meanwhile, we used SO staining, immunofluorescence, and immunohistochemical staining to evaluate the pharmacological effects of ECH in mice in vivo. Results. We demonstrated the effectiveness of ECH in suppressing ER stress and restoring ECM metabolism in vitro. In particular, ECH was shown to suppress tert-Butyl hydroperoxide- (TBHP-) induced OS and subsequently lower the levels of p-PERK/PERK, GRP78, ATF4, p-eIF2α/eIF2α, and CHOP in vitro. Simultaneously, ECH reduced MMP13 and ADAMTS5 levels and promoted Aggrecan and Collagen II levels, suggesting ECM degradation suppression. Moreover, we showed that ECH mediates its cellular effects via upregulation of Sirt1. Lastly, we confirmed that ECH can protect against OA in mouse OA models. Conclusion. In summary, our findings indicate that ECH can inhibit ER stress and ECM degradation by upregulating Sirt1 in mouse chondrocytes treated with TBHP. It can also prevent OA development in vivo.

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sFlt-1 commutes unfolded protein response into endoplasmic reticulum stress in trophoblast cells in preeclamptic pregnancies

10.1101/297374 ◽

2018 ◽

Author(s):

Sankat Mochan ◽

Manoj Kumar Dhingra ◽

Sunil Kumar Gupta ◽

Shobhit saxena ◽

Pallavi Arora ◽

...

Keyword(s):

Oxidative Stress ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Er Stress ◽

Late Onset ◽

Trophoblast Cells ◽

Bewo Cells ◽

Placental Cells

AbstractPreeclampsia (PE) and its subtypes (early and late onset) are serious concerns all across the globe affecting about 8% of total pregnancies and accounts for approximately 60,000 deaths annually with a predominance in developing under-developed and countries. The two-stage model in the progression of this disease, deficient spiral artery remodelling and an imbalance between angiogenic (VEGF) and anti-antigenic factor(s) (sFlt-1) are well established facts pertaining to this disease. The presence of increased sFlt-1, high oxidative stress and Endoplasmic reticulum stress (ER stress) have been proposed in preeclamptic pregnancies. Recently, the role of endoplasmic reticulum stress in the onset of the variant forms of PE highlighted a new window to explore further. In our previous studies, we demonstrated that sFlt-1 can induce apoptosis and oxidative stress in trophoblast cells. However the role of sFlt-1, in inducing ER stress is not known so far. In the present study, we for the first time demonstrated significant ER stress in the placental cells (BeWo Cells) (in vitro) when exposed to sera from preeclamptic pregnancies having increased concentration of sFlt-1. The expression of ER stress markers (GRP78, eIF2α, XBP1, ATF6 and CHOP) at both transcript and protein levels were compared (between preeclamptic and normotensive non-proteinuric women) at three different time points (8h, 14h and 24hrs), analyzed and found to be significant (p<0.05).ConclusionOur results suggested that sFlt-1, released from placental cells in preeclampsia may be one of the various factors having potential to induce endoplasmic reticulum stress in BeWo cells.

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