scholarly journals Endoplasmic reticulum proteostasis: a key checkpoint in cancer

2017 ◽  
Vol 312 (2) ◽  
pp. C93-C102 ◽  
Author(s):  
Scott A. Oakes
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cancer Cells ◽  
Intracellular Signaling ◽  
Secretory Pathway ◽  
Cell Types ◽  
Extrinsic Factors ◽  
Targeted Interventions ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response

The unfolded protein response (UPR) is an intracellular signaling network largely controlled by three endoplasmic reticulum (ER) transmembrane proteins, inositol-requiring enzyme 1α, PRK-like ER kinase, and activating transcription factor 6, that monitor the protein-folding status of the ER and initiate corrective measures to maintain ER homeostasis. Hypoxia, nutrient deprivation, proteasome dysfunction, sustained demands on the secretory pathway or somatic mutations in its client proteins, conditions often encountered by cancer cells, can lead to the accumulation of misfolded proteins in the ER and cause “ER stress.” Under remediable levels of ER stress, the homeostatic UPR outputs activate transcriptional and translational changes that promote cellular adaptation. However, if the ER stress is irreversible despite these measures, a terminal UPR program supersedes that actively signals cell destruction. In addition to its prosurvival and prodeath outputs, the UPR is now recognized to play a major role in the differentiation and activation of specific immune cells, as well as proinflammatory cytokine production in many cell types. Given the numerous intrinsic and extrinsic factors that threaten the fidelity of the secretory pathway in cancer cells, it is not surprising that ER stress is documented in many solid and hematopoietic malignancies, but whether ongoing UPR signaling is beneficial or detrimental to tumor growth remains hotly debated. Here I review recent evidence that cancer cells are prone to loss of proteostasis within the ER, and hence may be susceptible to targeted interventions that either reduce homeostatic UPR outputs or alternatively trigger the terminal UPR.

scholarly journals The Role of Endoplasmic Reticulum Stress in Cardiovascular Disease and Exercise

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
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.

scholarly journals Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

2008 ◽  
Vol 199 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Ernest Sargsyan ◽  
Henrik Ortsäter ◽  
Kristofer Thorn ◽  
Peter Bergsten
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Er Stress ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Eukaryotic Translation ◽  
Β Cell Function ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response

Elevated levels of glucose and lipids are characteristics of individuals with type 2 diabetes mellitus (T2DM). The enhanced nutrient levels have been connected with deterioration of β-cell function and impaired insulin secretion observed in these individuals. A strategy to improve β-cell function in individuals with T2DM has been intermittent administration of KATP channel openers. After such treatment, both the magnitude and kinetics of insulin secretion are markedly improved. In an attempt to further delineate mechanisms of how openers of KATP channels improve β-cell function, the effects of diazoxide on markers of endoplasmic reticulum (ER) stress was determined in β-cells exposed to the fatty acid palmitate. The eukaryotic translation factor 2-alpha kinase 3 (EIF2AK3; also known as PERK) and endoplasmic reticulum to nucleus signaling 1 (ERN1; also known as IRE1) pathways, but not the activating transcription factor (ATF6) pathway of the unfolded protein response, are activated in such lipotoxic β-cells. Inclusion of diazoxide during culture attenuated activation of the EIF2AK3 pathway but not the ERN1 pathway. This attenuation was associated with reduced levels of DNA-damage inducible transcript 3 (DDIT3; also known as CHOP) and β-cell apoptosis was decreased. It is concluded that reduction of ER stress may be a mechanism by which diazoxide improves β-cell function.

scholarly journals A Nudibranch Marine Extract Selectively Chemosensitizes Colorectal Cancer Cells by Inducing ROS-Mediated Endoplasmic Reticulum Stress

2021 ◽  
Vol 12 ◽  
Author(s):  
Verónica Ruiz-Torres ◽  
Nicholas Forsythe ◽  
Almudena Pérez-Sánchez ◽  
Sandra Van Schaeybroeck ◽  
Enrique Barrajón-Catalán ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cancer Cells ◽  
Human Colon ◽  
Resistance Mechanisms ◽  
Colon Cancer Cells ◽  
Colon Cells ◽  
Lower Effect ◽  
The Unfolded Protein Response

The present study shows the putative antiproliferative mechanism of action of the previously analytically characterized nudibranch extract ( Dolabella auricularia, NB) and its different effects in colon cancer cells vs. nontumor colon cells. NB extract increased the accumulation of reactive oxygen species (ROS) and increased endoplasmic reticulum (ER) stress via stimulation of the unfolded protein response. Stress scavengers, N-acetylcysteine (NAC) and 4-phenylbutyric acid (4-PBA), decreased the stress induced by NB. The results showed that NB extract increased ER stress through overproduction of ROS in superinvasive colon cancer cells, decreased their resistance threshold, and produced a nonreturn level of ER stress, causing DNA damage and cell cycle arrest, which prevented them from achieving hyperproliferative capacity and migrating to and invading other tissues. On the contrary, NB extract had a considerably lower effect on nontumor human colon cells, suggesting a selective effect related to stress balance homeostasis. In conclusion, our results confirm that the growth and malignancy of colon cancer cells can be decreased by marine compounds through the modification of one of the most potent resistance mechanisms present in tumor cells; this characteristic differentiates cancer cells from nontumor cells in terms of stress balance.

Pancreatic β-cells depend on basal expression of active ATF6α-p50 for cell survival even under nonstress conditions

2012 ◽  
Vol 302 (7) ◽  
pp. C992-C1003 ◽  
Author(s):  
Tracy Teodoro ◽  
Tanya Odisho ◽  
Elena Sidorova ◽  
Allen Volchuk
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Cell Survival ◽  
Protein Levels ◽  
Unfolded Protein ◽  
Basal Expression ◽  
Steady State Levels ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Insulinoma Cells

Activating transcription factor 6 (ATF6) is one of three principle endoplasmic reticulum (ER) stress response proteins and becomes activated when ER homeostasis is perturbed. ATF6 functions to increase ER capacity by stimulating transcription of ER-resident chaperone genes such as GRP78. Using an antibody that recognizes active ATF6α-p50, we found that active ATF6α was detected in insulinoma cells and rodent islets even under basal conditions and the levels were further increased by ER stress. To examine the function of ATF6α-p50, we depleted endogenous ATF6α-p50 levels using small interfering RNA in insulinoma cells. Knockdown of endogenous ATF6α-p50 levels by ∼60% resulted in a reduction in the steady-state levels of GRP78 mRNA and protein levels in nonstressed cells. Furthermore, ATF6α knockdown resulted in an apoptotic phenotype. We hypothesized that removal of the ATF6α branch of the unfolded protein response (UPR) would result in ER stress. However, neither the PKR-like endoplasmic reticulum kinase (PERK), nor the inositol requiring enzyme 1 (IRE1) pathways of the UPR were significantly activated in ATF6α knockdown cells, although these cells were more sensitive to ER stress-inducing compounds. Interestingly, phosphorylation of JNK, p38, and c-Jun were elevated in ATF6α knockdown cells and inhibition of JNK or p38 kinases prevented apoptosis. These results suggest that ATF6α may have a role in maintaining β-cell survival even in the absence of ER stress.

Endoplasmic Reticulum Stress Signaling Pathways: Activation and Diseases

2019 ◽  
Vol 20 (9) ◽  
pp. 935-943 ◽  
Author(s):  
Zhi Zheng ◽  
Yuxi Shang ◽  
Jiahui Tao ◽  
Jun Zhang ◽  
Bingdong Sha
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Misfolded Proteins ◽  
Endogenous Factors ◽  
Unfolded Protein ◽  
Dependent Protein ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Sensor Molecules

Secretory and membrane proteins are folded in the endoplasmic reticulum (ER) prior to their exit. When ER function is disturbed by exogenous and endogenous factors, such as heat shock, ultraviolet radiation, hypoxia, or hypoglycemia, the misfolded proteins may accumulate, promoting ER stress. To rescue this unfavorable situation, the unfolded protein response is activated to reduce misfolded proteins within the ER. Upon ER stress, the ER transmembrane sensor molecules inositol-requiring enzyme 1 (IRE1), RNA-dependent protein kinase (PKR)-like ER kinase (PERK), and activating transcription factor 6, are activated. Here, we discuss the mechanisms of PERK and IRE1 activation and describe two working models for ER stress initiation: the BiP-dependent model and the ligand-driven model. ER stress activation has been linked to multiple diseases, including cancers, Alzheimer’s disease, and diabetes. Thus, the regulation of ER stress may provide potential therapeutic targets for these diseases.

scholarly journals BiP Availability Distinguishes States of Homeostasis and Stress in the Endoplasmic Reticulum of Living Cells

2010 ◽  
Vol 21 (12) ◽  
pp. 1909-1921 ◽  
Author(s):  
Chun Wei Lai ◽  
Deborah E. Aronson ◽  
Erik Lee Snapp
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Misfolding ◽  
Single Cells ◽  
Cell Types ◽  
Secretory Protein ◽  
Misfolded Proteins ◽  
Secretory Proteins ◽  
Molecular Events ◽  
The Unfolded Protein Response

Accumulation of misfolded secretory proteins causes cellular stress and induces the endoplasmic reticulum (ER) stress pathway, the unfolded protein response (UPR). Although the UPR has been extensively studied, little is known about the molecular changes that distinguish the homeostatic and stressed ER. The increase in levels of misfolded proteins and formation of complexes with chaperones during ER stress are predicted to further crowd the already crowded ER lumen. Surprisingly, using live cell fluorescence microscopy and an inert ER reporter, we find the crowdedness of stressed ER, treated acutely with tunicamycin or DTT, either is comparable to homeostasis or significantly decreases in multiple cell types. In contrast, photobleaching experiments revealed a GFP-tagged variant of the ER chaperone BiP rapidly undergoes a reversible quantitative decrease in diffusion as misfolded proteins accumulate. BiP mobility is sensitive to exceptionally low levels of misfolded protein stressors and can detect intermediate states of BiP availability. Decreased BiP availability temporally correlates with UPR markers, but restoration of BiP availability correlates less well. Thus, BiP availability represents a novel and powerful tool for reporting global secretory protein misfolding levels and investigating the molecular events of ER stress in single cells, independent of traditional UPR markers.

scholarly journals Endoplasmic Reticulum Stress-induced mRNA Splicing Permits Synthesis of Transcription Factor Hac1p/Ern4p That Activates the Unfolded Protein Response

1997 ◽  
Vol 8 (10) ◽  
pp. 1845-1862 ◽  
Author(s):  
Tetsushi Kawahara ◽  
Hideki Yanagi ◽  
Takashi Yura ◽  
Kazutoshi Mori
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Intracellular Signaling ◽  
Mrna Splicing ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Precursor Mrna

An intracellular signaling from the endoplasmic reticulum (ER) to the nucleus, called the unfolded protein response (UPR), is activated when unfolded proteins are accumulated in the ER under a variety of stress conditions (“ER stress”). We and others recently identified Hac1p/Ern4p as a transcription factor responsible for the UPR inSaccharomyces cerevisiae. It was further reported that Hac1p (238 aa) is detected only in ER-stressed cells, and its expression is mediated by unconventional splicing ofHAC1 precursor mRNA. The splicing replaces the C-terminal portion of Hac1p; it was proposed that precursor mRNA is also translated but the putative product of 230 aa is rapidly degraded by the ubiquitin–proteasome pathway. We have identified and characterized the same regulated splicing and confirmed its essential features. Contrary to the above proposal, however, we find that the 238-aa product of mature mRNA and the 230-aa-type protein tested are highly unstable with little or no difference in stability. Furthermore, we demonstrate that the absence of Hac1p in unstressed cells is due to the lack of translation of precursor mRNA. We conclude that Hac1p is synthesized as the result of ER stress-induced mRNA splicing, leading to activation of the UPR.

scholarly journals Link between endoplasmic reticulum stress and autophagy in neurodegenerative diseases

2017 ◽  
Vol 4 (1) ◽  
Author(s):  
Toru Hosoi ◽  
Jun Nomura ◽  
Keigo Tanaka ◽  
Koichiro Ozawa ◽  
Akinori Nishi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Brain Function ◽  
Review Article ◽  
Double Stranded Rna ◽  
Unfolded Protein ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractIncreasing evidence suggests that endoplasmic reticulum (ER) stress and autophagy play an important role in regulating brain function. ER stress activates three major branches of the unfolded protein response (UPR) pathways, namely inositol-requiring enzyme-1 (IRE1), double stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) and activating transcription factor 6 (ATF6)-mediated pathways. Recent studies have suggested that these UPR signals may be linked to autophagy. In this review article, we summarize recent evidence and discuss a possible link between ER stress and autophagy with regard to neurodegenerative diseases. Furthermore, possible pharmacological strategies targeting UPR and autophagy are discussed.

scholarly journals Functional Coupling between the Unfolded Protein Response and Endoplasmic Reticulum/Golgi Ca2+-ATPases Promotes Stress Tolerance, Cell Wall Biosynthesis, and Virulence of Aspergillus fumigatus

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Martin Weichert ◽  
José Guirao-Abad ◽  
Vishukumar Aimanianda ◽  
Karthik Krishnan ◽  
Christina Grisham ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Wall ◽  
Er Stress ◽  
Aspergillus Fumigatus ◽  
Secretory Pathway ◽  
Functional Coupling ◽  
Content Type ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT Many species of pathogenic fungi deploy the unfolded protein response (UPR) to expand the folding capacity of the endoplasmic reticulum (ER) in proportion to the demand for virulence-related proteins that traffic through the secretory pathway. Although Ca2+ plays a pivotal role in ER function, the mechanism by which transcriptional upregulation of the protein folding machinery is coordinated with Ca2+ homeostasis is incompletely understood. In this study, we investigated the link between the UPR and genes encoding P-type Ca2+-ATPases in the human-pathogenic mold Aspergillus fumigatus. We demonstrate that acute ER stress increases transcription of the srcA gene, encoding a member of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) family, as well as that of pmrA, encoding a secretory pathway Ca2+-ATPase (SPCA) in the Golgi membrane. Loss of the UPR transcription factor HacA prevented the induction of srcA and pmrA transcription during ER stress, defining these ER/Golgi Ca2+ pumps as novel downstream targets of this pathway. While deletion of srcA alone caused no major deficiencies, a ΔsrcA/ΔpmrA mutant displayed a severe polarity defect, was hypersensitive to ER stress, and showed attenuated virulence. In addition, cell wall analyses revealed a striking reduction in mannose levels in the absence of both Ca2+ pumps. The ΔhacA mutant was hypersensitive to agents that block calcineurin-dependent signaling, consistent with a functional coupling between the UPR and Ca2+ homeostasis. Together, these findings demonstrate that the UPR integrates the need for increased levels of chaperone and folding enzymes with an influx of Ca2+ into the secretory pathway to support fungal growth, stress adaptation, and pathogenicity. IMPORTANCE The UPR is an intracellular signal transduction pathway that maintains homeostasis of the ER. The pathway is also tightly linked to the expression of virulence-related traits in diverse species of human-pathogenic and plant-pathogenic fungal species, including the predominant mold pathogen infecting humans, Aspergillus fumigatus. Despite advances in the understanding of UPR signaling, the linkages and networks that are governed by this pathway are not well defined. In this study, we revealed that the UPR is a major driving force for stimulating Ca2+ influx at the ER and Golgi membranes and that the coupling between the UPR and Ca2+ import is important for virulence, cell wall biosynthesis, and resistance to antifungal compounds that inhibit Ca2+ signaling.

scholarly journals Divest Yourself of a Preconceived Idea: Transcription Factor ATF6 Is Not a Soluble Protein!

2010 ◽  
Vol 21 (9) ◽  
pp. 1435-1438 ◽  
Author(s):  
Kazutoshi Mori
Keyword(s):  
Transcription Factor ◽  
Er Stress ◽  
Transcriptional Activation ◽  
Intracellular Signaling ◽  
Leucine Zipper ◽  
Transmembrane Protein ◽  
Basic Leucine Zipper ◽  
Induction Program ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response

The unfolded protein response (UPR), an evolutionarily conserved transcriptional induction program that is coupled with intracellular signaling from the endoplasmic reticulum (ER) to the nucleus, is activated to cope with ER stress and to maintain the homeostasis of the ER. In 1996, we isolated a basic leucine zipper protein, which had been previously named activating transcription factor (ATF)6, as a candidate transcription factor responsible for the mammalian UPR. Subsequent analysis, however, was confounding. The problem was eventually tracked down to an unusual property of ATF6: rather than being a soluble nuclear protein, as expected for an active transcription factor, ATF6 was instead synthesized as a transmembrane protein embedded in the ER, which was activated by ER stress-induced proteolysis. ATF6 was thus unique: an ER stress sensor/transducer that is involved in all steps of the UPR, from the sensing step in the ER to the transcriptional activation step in the nucleus.

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