scholarly journals Role of ERO1-α–mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress–induced apoptosis

2009 ◽  
Vol 186 (6) ◽  
pp. 783-792 ◽  
Author(s):  
Gang Li ◽  
Marco Mongillo ◽  
King-Tung Chin ◽  
Heather Harding ◽  
David Ron ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Calcium Release ◽  
Loss Of Function ◽  
Ip3 Receptor ◽  
Calcium Dependent ◽  
Insulin Resistant ◽  
Stressed Cells ◽  
Induced Apoptosis

Endoplasmic reticulum (ER) stress–induced apoptosis is involved in many diseases, but the mechanisms linking ER stress to apoptosis are incompletely understood. Based on roles for C/EPB homologous protein (CHOP) and ER calcium release in apoptosis, we hypothesized that apoptosis involves the activation of inositol 1,4,5-triphosphate (IP3) receptor (IP3R) via CHOP-induced ERO1-α (ER oxidase 1 α). In ER-stressed cells, ERO1-α is induced by CHOP, and small interfering RNA (siRNA) knockdown of ERO1-α suppresses apoptosis. IP3-induced calcium release (IICR) is increased during ER stress, and this response is blocked by siRNA-mediated silencing of ERO1-α or IP3R1 and by loss-of-function mutations in Ero1a or Chop. Reconstitution of ERO1-α in Chop−/− macrophages restores ER stress–induced IICR and apoptosis. In vivo, macrophages from wild-type mice but not Chop−/− mice have elevated IICR when the animals are challenged with the ER stressor tunicamycin. Macrophages from insulin-resistant ob/ob mice, another model of ER stress, also have elevated IICR. These data shed new light on how the CHOP pathway of apoptosis triggers calcium-dependent apoptosis through an ERO1-α–IP3R pathway.

scholarly journals Polyphenol-rich extract induces apoptosis with immunogenic markers in melanoma cells through the ER stress-associated kinase PERK

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Karol Prieto ◽  
Yu Cao ◽  
Eslam Mohamed ◽  
Jimena Trillo-Tinoco ◽  
Rosa A. Sierra ◽  
...  
Keyword(s):  
Er Stress ◽  
Stress Responses ◽  
Calcium Release ◽  
Melanoma Cells ◽  
Melanoma Tumor ◽  
Cancer Cell Death ◽  
Extracellular Release ◽  
Induced Apoptosis ◽  
Stress Mediators

Abstract Polyphenols elicit antitumor activities, in part, through the induction of anti- or pro-oxidant effects in cancer cells which promote priming of protective anti-tumor immunity. We recently characterized a polyphenol-rich extract from Caesalpinia spinosa (P2Et) that stimulates in vivo antitumor responses against breast and melanoma tumor models via the promotion of immunogenic cancer cell death (ICD). However, the primary mediators whereby P2Et promotes ICD remained unknown. Here, we sought to elucidate the role that severe endoplasmic reticulum (ER) stress plays in mediating P2Et-induced apoptosis and ICD in murine melanoma cells. Our findings demonstrate a substantial selective induction of specific ER-stress mediators in B16-F10 melanoma cells treated with P2Et. While knockout of the ER stress-associated PKR-like ER kinase (PERK) prevented induction of apoptosis and expression of ICD markers in P2Et-treated cells, deletion of X-box binding protein 1 (Xbp1) did not. P2Et-driven activation of PERK in melanoma cells was found to promote ER-calcium release, disrupt mitochondrial membrane potential, and trigger upregulation of ICD drivers, surface calreticulin expression, and extracellular release of ATP and HMGB1. Notably, calcium release inhibition, but not targeting of PERK-driven integrated stress responses, prevented P2Et-induced apoptosis. Collectively, these results underline the central role of PERK-directed calcium release in mediating the antitumor and immunogenic actions of P2Et in melanoma cells.

scholarly journals p31 Deficiency Influences Endoplasmic Reticulum Tubular Morphology and Cell Survival

2009 ◽  
Vol 29 (7) ◽  
pp. 1869-1881 ◽  
Author(s):  
Takefumi Uemura ◽  
Takashi Sato ◽  
Takehiro Aoki ◽  
Akitsugu Yamamoto ◽  
Tetsuya Okada ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Nuclear Translocation ◽  
Marked Change ◽  
Conditional Knockout ◽  
Induced Apoptosis ◽  
Factor C ◽  
Er Membrane

ABSTRACT p31, the mammalian orthologue of yeast Use1p, is an endoplasmic reticulum (ER)-localized soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) that forms a complex with other SNAREs, particularly syntaxin 18. However, the role of p31 in ER function remains unknown. To determine the role of p31 in vivo, we generated p31 conditional knockout mice. We found that homozygous deletion of the p31 gene led to early embryonic lethality before embryonic day 8.5. Conditional knockout of p31 in brains and mouse embryonic fibroblasts (MEFs) caused massive apoptosis accompanied by upregulation of ER stress-associated genes. Microscopic analysis showed vesiculation and subsequent enlargement of the ER membrane in p31-deficient cells. This type of drastic disorganization in the ER tubules has not been demonstrated to date. This marked change in ER structure preceded nuclear translocation of the ER stress-related transcription factor C/EBP homologous protein (CHOP), suggesting that ER stress-induced apoptosis resulted from disruption of the ER membrane structure. Taken together, these results suggest that p31 is an essential molecule involved in the maintenance of ER morphology and that its deficiency leads to ER stress-induced apoptosis.

scholarly journals Prevention of glucocorticoid induced-apoptosis of osteoblasts and osteocytes by protecting against endoplasmic reticulum (ER) stress in vitro and in vivo in female mice

Bone ◽  
2015 ◽  
Vol 73 ◽  
pp. 60-68 ◽  
Author(s):  
Amy Y. Sato ◽  
Xiaolin Tu ◽  
Kevin A. McAndrews ◽  
Lilian I. Plotkin ◽  
Teresita Bellido
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Female Mice ◽  
Induced Apoptosis

The life span of short-lived plasma cells is partly determined by a block on activation of apoptotic caspases acting in combination with endoplasmic reticulum stress

Blood ◽  
2010 ◽  
Vol 116 (18) ◽  
pp. 3445-3455 ◽  
Author(s):  
Holger W. Auner ◽  
Christine Beham-Schmid ◽  
Niall Dillon ◽  
Pierangela Sabbattini
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Caspase 3 ◽  
Plasma Cells ◽  
Myeloma Cell ◽  
Immunoglobulin Secretion ◽  
Effector Caspase ◽  
Induced Apoptosis

Abstract Apoptosis of short-lived plasma cells after a few days of intense immunoglobulin secretion is critical for maintaining a controlled humoral immune response. The mechanisms that regulate this process are poorly understood. Here we report that the key apoptotic caspases, caspase-3 and caspase-9, become resistant to activation by apoptotic stimuli when B cells differentiate into short-lived plasma cells. As a consequence, apoptosis of most short-lived plasma cells in vitro and in vivo is effector caspase-independent. We also show that a triaspartic acid repeat that normally prevents activation of caspase-3 becomes stabilized in short-lived plasma cells and myeloma cell lines. The block on caspase activation occurs before the accumulation of intracellular immunoglobulins and a progressive rise in secretory stress in the endoplasmic reticulum (ER). Plasma cells show increased susceptibility to ER stress–induced apoptosis and activate the ER-associated caspase-12, which is required specifically for nuclear apoptotic events. In nonlymphoid cells that cannot activate effector caspases, programmed cell death is delayed in response to ER stress. These observations suggest that the block on activation of key apoptotic caspases has evolved in short-lived plasma cells to prolong survival under conditions of ER stress resulting from high-level immunoglobulin secretion.

scholarly journals α-Mangostin Induces Apoptosis in Human Osteosarcoma Cells Through ROS-Mediated Endoplasmic Reticulum Stress via the WNT Pathway

2021 ◽  
Vol 30 ◽  
pp. 096368972110350
Author(s):  
Shengsen Yang ◽  
Fei Zhou ◽  
Yi Dong ◽  
Fei Ren
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Caspase 3 ◽  
Marker Proteins ◽  
Human Osteosarcoma Cells ◽  
Ros Accumulation ◽  
Normal Human ◽  
Induced Apoptosis ◽  
Normal Human Osteoblast

α-mangostin has been confirmed to promote the apoptosis of MG-63 cells, but its specific pro-apoptosis mechanism in osteosarcoma (OS) remains further investigation. Here, we demonstrated that α-mangostin restrained the viability of OS cells (143B and Saos-2), but had little effect on the growth of normal human osteoblast. α-mangostin increased OS cell apoptosis by activating the caspase-3/8 cascade. Besides, α-mangostin induced endoplasmic reticulum (ER) stress and restrained the Wnt/β-catenin pathway activity. 4PBA (an ER stress inhibitor) or LiCl (an effective Wnt activator) treatment effectively hindered α-mangostin-induced apoptosis and the caspase-3/8 cascade. Furthermore, we also found that α-mangostin induced ER stress by promoting ROS production. And ER stress-mediated apoptosis caused by ROS accumulation depended on the inactivation of Wnt/β-catenin pathway. In addition, α-mangostin significantly hindered the growth of xenograft tumors, induced the expression of ER stress marker proteins and activation of the caspase-3/8 cascade, and restrained the Wnt/β-catenin signaling in vivo. In short, ROS-mediated ER stress was involved in α-mangostin triggered apoptosis, which might depended on Wnt/β-catenin signaling inactivation.

scholarly journals Tauroursodeoxycholic acid prevents Burkholderia pseudomallei-induced endoplasmic reticulum stress and is protective during melioidosis in mice

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Siqi Yuan ◽  
Yao Fang ◽  
Mengling Tang ◽  
Zhiqiang Hu ◽  
Chenglong Rao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Burkholderia Pseudomallei ◽  
Treatment Strategies ◽  
Effective Vaccine ◽  
Tauroursodeoxycholic Acid ◽  
Raw264.7 Macrophages ◽  
Induced Apoptosis

Abstract Background Burkholderia pseudomallei, a facultative intracellular bacterium, is the aetiological agent of melioidosis that is responsible for up to 40% sepsis-related mortality in epidemic areas. However, no effective vaccine is available currently, and the drug resistance is also a major problem in the treatment of melioidosis. Therefore, finding new clinical treatment strategies in melioidosis is extremely urgent. Results We demonstrated that tauroursodeoxycholic acid (TUDCA), a clinically available endoplasmic reticulum (ER) stress inhibitor, can promote B. pseudomallei clearance both in vivo and in vitro. In this study, we investigated the effects of TUDCA on the survival of melioidosis mice, and found that treatment with TUDCA significantly decreased intracellular survival of B. pseudomallei. Mechanistically, we found that B. pseudomallei induced apoptosis and activated IRE1 and PERK signaling ways of ER stress in RAW264.7 macrophages. TUDCA treatment could reduce B. pseudomallei-induced ER stress in vitro, and TUDCA is protective in vivo. Conclusion Taken together, our study has demonstrated that B. pseudomallei infection results in ER stress-induced apoptosis, and TUDCA enhances the clearance of B. pseudomallei by inhibiting ER stress-induced apoptosis both in vivo and in vitro, suggesting that TUDCA could be used as a potentially alternative treatment for melioidosis.

scholarly journals Gambogenic Acid Induces Endoplasmic Reticulum Stress in Colorectal Cancer via the Aurora A Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Cheng Liu ◽  
Jiaxin Xu ◽  
Chenxu Guo ◽  
Xugang Chen ◽  
Chunmei Qian ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Aurora A ◽  
Eukaryotic Translation ◽  
Induced Apoptosis

Colorectal cancer (CRC) is one of the most common malignancies in the world and has a poor prognosis. In the present research, gambogenic acid (GNA), isolated from the traditional Chinese medicine gamboge, markedly induced apoptosis and inhibited the proliferation of CRC in vitro and in vivo. Furthermore, GNA triggered endoplasmic reticulum (ER) stress, which subsequently activated inositol-requiring enzyme (IRE) 1α and the eukaryotic translation initiation factor (eIF) 2α pathway. Pretreatment with salubrinal (an eIF2α inhibitor) rescued GNA-induced cell death. Furthermore, GNA downregulated the expression of Aurora A. The Aurora A inhibitor alisertib decreased ER stress. In human colorectal adenocarcinoma tissue, Aurora A was upregulated compared to normal colorectal epithelial nuclei. Furthermore, GNA ameliorated mouse colitis-associated cancer models. Our findings demonstrated that GNA significantly inhibited the proliferation of CRC through activation of ER stress by regulating Aurora A, which indicates the potential of GNA for preventing the progression of CRC.

scholarly journals NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis

2010 ◽  
Vol 191 (6) ◽  
pp. 1113-1125 ◽  
Author(s):  
Gang Li ◽  
Christopher Scull ◽  
Lale Ozcan ◽  
Ira Tabas
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Cellular Mechanisms ◽  
Apoptosis Pathway ◽  
Stress Oxidative ◽  
Induced Apoptosis ◽  
And Oxidative Stress

Endoplasmic reticulum (ER)–induced apoptosis and oxidative stress contribute to several chronic disease processes, yet molecular and cellular mechanisms linking ER stress and oxidative stress in the setting of apoptosis are poorly understood and infrequently explored in vivo. In this paper, we focus on a previously elucidated ER stress–apoptosis pathway whose molecular components have been identified and documented to cause apoptosis in vivo. We now show that nicotinamide adenine dinucleotide phosphate reduced oxidase (NOX) and NOX-mediated oxidative stress are induced by this pathway and that apoptosis is blocked by both genetic deletion of the NOX subunit NOX2 and by the antioxidant N-acetylcysteine. Unexpectedly, NOX and oxidative stress further amplify CCAAT/enhancer binding protein homologous protein (CHOP) induction through activation of the double-stranded RNA–dependent protein kinase (PKR). In vivo, NOX2 deficiency protects ER-stressed mice from renal cell CHOP induction and apoptosis and prevents renal dysfunction. These data provide new insight into how ER stress, oxidative stress, and PKR activation can be integrated to induce apoptosis in a pathophysiologically relevant manner.

scholarly journals Neuronal dystonin isoform 2 is a mediator of endoplasmic reticulum structure and function

2012 ◽  
Vol 23 (4) ◽  
pp. 553-566 ◽  
Author(s):  
Scott D. Ryan ◽  
Andrew Ferrier ◽  
Tadasu Sato ◽  
Ryan W. O'Meara ◽  
Yves De Repentigny ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Sensory Neurons ◽  
Stress Proteins ◽  
Function Analysis ◽  
Structure And Function ◽  
Loss Of Function ◽  
Specific Loss ◽  
And Function

Dystonin/Bpag1 is a cytoskeletal linker protein whose loss of function in dystonia musculorum (dt) mice results in hereditary sensory neuropathy. Although loss of expression of neuronal dystonin isoforms (dystonin-a1/dystonin-a2) is sufficient to cause dt pathogenesis, the diverging function of each isoform and what pathological mechanisms are activated upon their loss remains unclear. Here we show that dt27 mice manifest ultrastructural defects at the endoplasmic reticulum (ER) in sensory neurons corresponding to in vivo induction of ER stress proteins. ER stress subsequently leads to sensory neurodegeneration through induction of a proapoptotic caspase cascade. dt sensory neurons display neurodegenerative pathologies, including Ca2+ dyshomeostasis, unfolded protein response (UPR) induction, caspase activation, and apoptosis. Isoform-specific loss-of-function analysis attributes these neurodegenerative pathologies to specific loss of dystonin-a2. Inhibition of either UPR or caspase signaling promotes the viability of cells deficient in dystonin. This study provides insight into the mechanism of dt neuropathology and proposes a role for dystonin-a2 as a mediator of normal ER structure and function.

scholarly journals FBXO6-Mediated Ubiquitination and Degradation of Ero1L Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis

2016 ◽  
Vol 39 (6) ◽  
pp. 2501-2508 ◽  
Author(s):  
Xi Chen ◽  
Lang-Huan Duan ◽  
Peng-cheng Luo ◽  
Gang Hu ◽  
Xin Yu ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Critical Role ◽  
Dependent Manner ◽  
Ubiquitin E3 Ligase ◽  
The Stability ◽  
Induced Apoptosis ◽  
F Box Protein ◽  
Protein Disulfide

Background/Aims: FBXO6 is the substrate recognition component of a Skp1-Cullin1-F-box protein (SCF) ubiquitin E3 ligase complex, recognizing the chitobiose in unfolded N-glycoprotein to target glycoproteins for polyubiquitination and degradation. Although how FBXO6 recognizes glycoprotein has been fully investigated, the ubiquitination substrates of FBXO6 remain largely unknown. Previously, we have systematically identified the glycoproteins that interact with FBXO6 in an N-glycan dependent manner by LC/MS spectrum and confirmed the interaction between FBXO6 and glycosylated Ero1L, a protein disulfide oxidase in endoplasmic reticulum (ER). Methods: The relationship between endogenous Ero1L and exogenous Flag-FBXO6 were determined by Western blot. In vivo ubiquitination assay was used to detect the direct effect of FBXO6 in the regulation of Ero1L. Both CCK8 and FACS assays were used to determine the apoptosis ratio of cells after treatments. Results: Ero1L is a ubiquitination substrate of FBXO6. FBXO6 mediates the degradation of Ero1L through a ubiquitylation-dependent pathway. Overexpression of FBXO6 increased the polyubiquitination and decreased the stability of Ero1L, whereas inhibition of FBXO6 prolonged the half-life of Ero1L. Functionally, we show that FBXO6 inhibits ER stress-induced apoptosis by modulating the protein level of Ero1L. Conclusion: Collectively, our results demonstrate FBXO6 as a functional E3 ubiquitin ligase for Ero1L that plays a critical role in inhibiting ER stress-induced apoptosis.

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