scholarly journals Chronic Carbon Tetrachloride Applications Induced Hepatocyte Apoptosis in Lipocalin 2 Null Mice through Endoplasmic Reticulum Stress and Unfolded Protein Response

2020 ◽  
Vol 21 (15) ◽  
pp. 5230
Author(s):  
Erawan Borkham-Kamphorst ◽  
Ute Haas ◽  
Eddy Van de Leur ◽  
Anothai Trevanich ◽  
Ralf Weiskirchen
Keyword(s):  
Endoplasmic Reticulum ◽  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Er Stress ◽  
Stress Responses ◽  
Protein Glycosylation ◽  
Initiation Factor ◽  
Wild Type ◽  
Hepatocyte Apoptosis ◽  
Unfolded Protein

The lack of Lipocalin (LCN2) provokes overwhelming endoplasmic reticulum (ER) stress responses in vitro and in acute toxic liver injury models, resulting in hepatocyte apoptosis. LCN2 is an acute phase protein produced in hepatocytes in response to acute liver injuries. In line with these findings we investigated ER stress responses of Lcn2−/− mice in chronic ER stress using a long-term repetitive carbon tetrachloride (CCl4) injection model. We found chronic CCl4 application to enhance ER stress and unfolded protein responses (UPR), including phosphorylation of eukaryotic initiation factor 2α (eIF2α), increased expression of binding immunoglobulin protein (BiP) and glucose-regulated protein 94 (GRP94). IRE1α/TRAF2/JNK signaling enhanced mitochondrial apoptotic pathways, and showed slightly higher in Lcn2−/− mice compared to the wild type counterparts, leading to increased hepatocyte apoptosis well evidenced by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Hepatocyte injuries were confirmed by significant high serum alanine transaminase (ALT) levels in CCl4-treated Lcn2−/− mice. Lcn2−/− mice furthermore developed mild hepatic steatosis, supporting our finding that ER stress promotes lipogenesis. In a previous report we demonstrated that the pharmacological agent tunicamycin (TM) induced ER stress through altered protein glycosylation and induced high amounts of C/EBP-homologous protein (CHOP), resulting in hepatocyte apoptosis. We compared TM-induced ER stress in wild type, Lcn2−/−, and Chop null (Chop−/−) primary hepatocytes and found Chop−/− hepatocytes to attenuate ER stress responses and resist ER stress-induced hepatocyte apoptosis through canonical eIF2α/GADD34 signaling, inhibiting protein synthesis. Unexpectedly, in later stages of TM incubation, Chop−/− hepatocytes resumed activation of IRE1α/JNK/c-Jun and p38/ATF2 signaling, leading to late hepatocyte apoptosis. This interesting observation indicates Chop−/− mice to be unable to absolutely prevent all types of liver injury, while LCN2 protects the hepatocytes by maintaining homeostasis under ER stress conditions.

scholarly journals Deficiency in the double-stranded RNA binding protein HYPONASTIC LEAVES1 increases sensitivity to the endoplasmic reticulum stress inducer tunicamycin in Arabidopsis

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Rikako Hirata ◽  
Kei-ichiro Mishiba ◽  
Nozomu Koizumi ◽  
Yuji Iwata
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Stress Responses ◽  
Rna Binding ◽  
Transcriptional Response ◽  
Mirna Biogenesis ◽  
Loss Of Function ◽  
Wild Type ◽  
Protein Coding ◽  
And Function

Abstract Objective microRNA (miRNA) is a small non-coding RNA that regulates gene expression by sequence-dependent binding to protein-coding mRNA in eukaryotic cells. In plants, miRNA plays important roles in a plethora of physiological processes, including abiotic and biotic stress responses. The present study was conducted to investigate whether miRNA-mediated regulation is important for the endoplasmic reticulum (ER) stress response in Arabidopsis. Results We found that hyl1 mutant plants are more sensitive to tunicamycin, an inhibitor of N-linked glycosylation that causes ER stress than wild-type plants. Other miRNA-related mutants, se and ago1, exhibited similar sensitivity to the wild-type, indicating that the hypersensitive phenotype is attributable to the loss-of-function of HYL1, rather than deficiency in general miRNA biogenesis and function. However, the transcriptional response of select ER stress-responsive genes in hyl1 mutant plants was indistinguishable from that of wild-type plants, suggesting that the loss-of-function of HYL1 does not affect the ER stress signaling pathways.

scholarly journals Human Cytomegalovirus Protein pUL38 Induces ATF4 Expression, Inhibits Persistent JNK Phosphorylation, and Suppresses Endoplasmic Reticulum Stress-Induced Cell Death

2009 ◽  
Vol 83 (8) ◽  
pp. 3463-3474 ◽  
Author(s):  
Baoqin Xuan ◽  
Zhikang Qian ◽  
Emi Torigoi ◽  
Dong Yu
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Human Cytomegalovirus ◽  
Initiation Factor ◽  
Α Subunit ◽  
Unfolded Protein ◽  
Initiation Factor 2 ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT The endoplasmic reticulum (ER) is a key organelle involved in sensing and responding to stressful conditions, including those resulting from infection of viruses, such as human cytomegalovirus (HCMV). Three signaling pathways collectively termed the unfolded protein response (UPR) are activated to resolve ER stress, but they will also lead to cell death if the stress cannot be alleviated. HCMV is able to modulate the UPR to promote its infection. The specific viral factors involved in such HCMV-mediated modulation, however, were unknown. We previously showed that HCMV protein pUL38 was required to maintain the viability of infected cells, and it blocked cell death induced by thapsigargin. Here, we report that pUL38 is an HCMV-encoded regulator to modulate the UPR. In infection, pUL38 allowed HCMV to upregulate phosphorylation of PKR-like ER kinase (PERK) and the α subunit of eukaryotic initiation factor 2 (eIF-2α), as well as induce robust accumulation of activating transcriptional factor 4 (ATF4), key components of the PERK pathway. pUL38 also allowed the virus to suppress persistent phosphorylation of c-Jun N-terminal kinase (JNK), which was induced by the inositol-requiring enzyme 1 pathway. In isolation, pUL38 overexpression elevated eIF-2α phosphorylation, induced ATF4 accumulation, limited JNK phosphorylation, and suppressed cell death induced by both thapsigargin and tunicamycin, two drugs that induce ER stress by different mechanisms. Importantly, ATF4 overexpression and JNK inhibition significantly reduced cell death in pUL38-deficient virus infection. Thus, pUL38 targets ATF4 expression and JNK activation, and this activity appears to be critical for protecting cells from ER stress induced by HCMV infection.

scholarly journals Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 108
Author(s):  
Hui Li ◽  
Wen Wen ◽  
Jia Luo
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Effective Treatment ◽  
Stress Responses ◽  
Treatment Strategies ◽  
Alcoholic Pancreatitis ◽  
Excessive Alcohol Consumption ◽  
Unfolded Protein ◽  
Novel Therapeutic Strategies ◽  
Protein Response

Pancreatitis and alcoholic pancreatitis are serious health concerns with an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here, we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR in developing novel therapeutic strategies for the disease.

scholarly journals APOL1 risk variants cause podocytes injury through enhancing endoplasmic reticulum stress

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Hongxiu Wen ◽  
Vinod Kumar ◽  
Xiqian Lan ◽  
Seyedeh Shadafarin Marashi Shoshtari ◽  
Judith M. Eng ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Kidney Diseases ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Wild Type ◽  
Eukaryotic Translation ◽  
Risk Variants ◽  
Eukaryotic Translation Initiation ◽  
Underlying Mechanisms

Two coding sequence variants (G1 and G2) of Apolipoprotein L1 (APOL1) gene have been implicated as a higher risk factor for chronic kidney diseases (CKD) in African Americans when compared with European Americans. Previous studies have suggested that the APOL1 G1 and G2 variant proteins are more toxic to kidney cells than the wild-type APOL1 G0, but the underlying mechanisms are poorly understood. To determine whether endoplasmic reticulum (ER) stress contributes to podocyte toxicity, we generated human podocytes (HPs) that stably overexpressed APOL1 G0, G1, or G2 (Vec/HPs, G0/HPs, G1/HPs, and G2/HPs). Propidium iodide staining showed that HP overexpressing the APOL1 G1 or G2 variant exhibited a higher rate of necrosis when compared with those overexpressing the wild-type G0 counterpart. Consistently, the expression levels of nephrin and podocin proteins were significantly decreased in the G1- or G2-overexpressing cells despite the maintenance of their mRNA expressions levels. In contrast, the expression of the 78-kDa glucose-regulated protein ((GRP78), also known as the binding Ig protein, BiP) and the phosphorylation of the eukaryotic translation initiation factor 1 (eIF1) were significantly elevated in the G1/HPs and G2/HPs, suggesting a possible occurrence of ER stress in these cells. Furthermore, ER stress inhibitors not only restored nephrin protein expression, but also provided protection against necrosis in G1/HPs and G2/HPs, suggesting that APOL1 risk variants cause podocyte injury partly through enhancing ER stress.

scholarly journals Multilevel regulation of endoplasmic reticulum stress responses in plants: where old roads and new paths meet

2019 ◽  
Vol 71 (5) ◽  
pp. 1659-1667 ◽  
Author(s):  
Taiaba Afrin ◽  
Danish Diwan ◽  
Katrina Sahawneh ◽  
Karolina Pajerowska-Mukhtar
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Stress Responses ◽  
Translational Control ◽  
Protein Quality ◽  
Unfolded Protein ◽  
Transcriptional Gene Regulation ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract The sessile lifestyle of plants requires them to cope with a multitude of stresses in situ. In response to diverse environmental and intracellular cues, plant cells respond by massive reprogramming of transcription and translation of stress response regulators, many of which rely on endoplasmic reticulum (ER) processing. This increased protein synthesis could exceed the capacity of precise protein quality control, leading to the accumulation of unfolded and/or misfolded proteins that triggers the unfolded protein response (UPR). Such cellular stress responses are multilayered and executed in different cellular compartments. Here, we will discuss the three main branches of UPR signaling in diverse eukaryotic systems, and describe various levels of ER stress response regulation that encompass transcriptional gene regulation by master transcription factors, post-transcriptional activities including cytoplasmic splicing, translational control, and multiple post-translational events such as peptide modifications and cleavage. In addition, we will discuss the roles of plant ER stress sensors in abiotic and biotic stress responses and speculate on the future prospects of engineering these signaling events for heightened stress tolerance.

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

2018 ◽  
Vol 115 (22) ◽  
pp. E5203-E5212 ◽  
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.

scholarly journals Inhibition of eIF2α Dephosphorylation Protects Hepatocytes from Apoptosis by Alleviating ER Stress in Acute Liver Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-16
Author(s):  
Yong-Jing Tang ◽  
Huan Chen ◽  
Yu Yi ◽  
Gui-Mei Chen ◽  
Fang-Wan Yang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Er Stress ◽  
Acute Liver Injury ◽  
Initiation Factor ◽  
Calcium Balance ◽  
Hepatocyte Apoptosis ◽  
Protein Kinase R ◽  
Chemical Chaperone ◽  
Initiation Factor 2 ◽  
Phenylbutyric Acid

Objectives. Protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α) is an important factor along the main pathways for endoplasmic reticulum (ER) stress-mediated apoptosis. In this study, we investigated the effects of eIF2α phosphorylation on hepatocyte apoptosis and the ER stress mechanisms in acute liver injury. Methods. eIF2α phosphorylation and apoptosis under ER stress were monitored and measured in male BALB/c mice with acute liver injury and human hepatocyte line LO2 cells. Results. Carbon tetrachloride (CCl4) administration triggered ER stress and hepatocyte apoptosis, as well as eIF2α phosphorylation in mice. Inhibition of eIF2α dephosphorylation, as the pretreatment with 4-phenylbutyric acid (chemical chaperone, ER stress inhibitor), mitigated CCl4-induced intrahepatic ER stress, apoptosis, and liver injury. In an ER stress model of LO2 cells induced by thapsigargin (disrupting ER calcium balance), inhibition of eIF2α dephosphorylation reduced ER stress and apoptosis, while PERK knockdown reduced eIF2α phosphorylation and exacerbated ER stress and apoptosis. Conclusions. eIF2α phosphorylation is one of the mechanisms employed by ER stress for restoring cellular homeostasis. Inhibition of eIF2α dephosphorylation mitigates hepatocyte apoptosis by alleviating ER stress in acute liver injuries.

scholarly journals Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis

2021 ◽  
Author(s):  
Hui Li ◽  
Wen Wen ◽  
Jia Luo
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Effective Treatment ◽  
Stress Responses ◽  
Treatment Strategies ◽  
Alcoholic Pancreatitis ◽  
Excessive Alcohol Consumption ◽  
Unfolded Protein ◽  
Novel Therapeutic Strategies ◽  
Protein Response

Pancreatitis and alcoholic pancreatitis are serious health concerns, and there is an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR for developing novel therapeutic strategies for the disease.

Hydrogen sulfide protects SH-SY5Y cells against 6-hydroxydopamine-induced endoplasmic reticulum stress

2012 ◽  
Vol 303 (1) ◽  
pp. C81-C91 ◽  
Author(s):  
Li Xie ◽  
Chi Xin Tiong ◽  
Jin-Song Bian
Keyword(s):  
Endoplasmic Reticulum ◽  
Hydrogen Sulfide ◽  
Protective Effect ◽  
Er Stress ◽  
Stress Responses ◽  
Initiation Factor ◽  
Akt Inhibitor ◽  
Stress Injury ◽  
Sodium Hydrosulfide ◽  
6 Hydroxydopamine

Endoplasmic reticulum (ER) stress has been implicated in several neurodegenerative diseases, including Parkinson's disease. The present study attempted to investigate the effect of hydrogen sulfide (H2S) on 6-hydroxydopamine (6-OHDA)-induced ER stress in SH-SY5Y cells. We found in the present study that exogenous application of sodium hydrosulfide (NaHS; an H2S donor, 100 μM) significantly attenuated 6-OHDA (50 μM)-induced cell death. NaHS also reversed the upregulation of cleaved poly(ADP-ribose) polymerase and caspase 9 in 6-OHDA-treated cells. Consistent with its cytoprotective effects, NaHS markedly reduced 6-OHDA induced-ER stress responses, including the upregulated levels of eukaryotic initiation factor-2α phosphorylation, glucose-regulated protein 78, and C/EBP homologous protein expression. The protective effect of H2S on ER stress was attenuated by blockade of Akt activity with an Akt inhibitor or inhibition of heat shock protein (Hsp)90 with geldanamycin but not by suppression of ERK1/2 with PD-98059. Blockade of Akt also significantly decreased the protein abundance of Hsp90 in SH-SY5Y cells. Moreover, overexpression of cystathionine β-synthase (a main H2S-synthesizing enzyme in the brain) elevated the Hsp90 protein level and suppressed 6-OHDA-induced ER stress. In conclusion, the protective effect of H2S against 6-OHDA-induced ER stress injury in SH-SY5Y cells involves the Akt-Hsp90 pathway.

scholarly journals APY-1, a Novel Caenorhabditis elegans Apyrase Involved in Unfolded Protein Response Signalling and Stress Responses

2008 ◽  
Vol 19 (4) ◽  
pp. 1337-1345 ◽  
Author(s):  
D. Uccelletti ◽  
A. Pascoli ◽  
F. Farina ◽  
A. Alberti ◽  
P. Mancini ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Stress Responses ◽  
Sugar Metabolism ◽  
Protein Glycosylation ◽  
Premature Aging ◽  
C Elegans ◽  
Unfolded Protein ◽  
Protein Response

Protein glycosylation modulates a wide variety of intracellular events and dysfunction of the glycosylation pathway has been reported in a variety of human pathologies. Endo-apyrases have been suggested to have critical roles in protein glycosylation and sugar metabolism. However, deciphering the physiological relevance of Endo-apyrases activity has actually proved difficult, owing to their complexity and the functional redundancy within the family. We report here that a UDP/GDPase, homologous to the human apyrase Scan-1, is present in the membranes of Caenorhabditis elegans, encoded by the ORF F08C6.6 and hereinafter-named APY-1. We showed that ER stress induced by tunicamycin or high temperature resulted in increased transcription of apy-1. This increase was not observed in C. elegans mutants defective in ire-1 or atf-6, demonstrating the requirement of both ER stress sensors for up-regulation of apy-1. Depletion of APY-1 resulted in constitutively activated unfolded protein response. Defects in the pharynx and impaired organization of thin fibers in muscle cells were observed in adult worms depleted of APY-1. Some of the apy-1(RNAi) phenotypes are suggestive of premature aging, because these animals also showed accumulation of lipofuscin and reduced lifespan that was not dependent on the functioning of DAF-2, the receptor of the insulin/IGF-1 signaling pathway.

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