scholarly journals Baldspot/ELOVL6 is a conserved modifier of disease and the ER stress response ELOVL6 modifies ER stress

2018 ◽  
Author(s):  
Rebecca A. S. Palu ◽  
Clement Y. Chow
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Genetic Variation ◽  
Stress Response ◽  
Er Stress ◽  
Chain Fatty Acid ◽  
Long Chain Fatty Acid ◽  
Fatty Acid Elongase ◽  
Er Stress Response ◽  
Long Chain

ABSTRACTEndoplasmic reticulum (ER) stress is an important modifier of human disease. Genetic variation in genes involved in the ER stress response has been linked to inter-individual differences in this response. However, the mechanisms and pathways by which genetic modifiers are acting on the ER stress response remain unclear. In this study, we characterize the role of the long chain fatty acid elongase Baldspot (ELOVL6) in modifying the ER stress response and disease. We demonstrate that loss of Baldspot rescues degeneration and reduces IRE1 and PERK signaling and cell death in a Drosophila model of retinitis pigmentosa and ER stress (Rh1G69D). Dietary supplementation of stearate bypasses the need for Baldspot activity. Finally, we demonstrate that Baldspot regulates the ER stress response across different tissues and induction methods. Our findings suggest that ELOVL6 is a promising target in the treatment of not only retinitis pigmentosa, but a number of different ER stress-related disorders.AUTHOR SUMMARYDifferences in genetic background drives disease variability, even among individuals with identical, causative mutations. Identifying and understanding how genetic variation impacts disease expression could improve diagnosis and treatment of patients. Previous work has linked the endoplasmic reticulum (ER) stress response pathway to disease variability. When misfolded proteins accumulate in the ER, the ER stress response returns the cell to its normal state. Chronic ER stress leads to massive amounts of cell death and tissue degeneration. Limiting tissue loss by regulating the ER stress response has been a major focus of therapeutic development. In this study, we characterize a novel regulator of the ER stress response, the long chain fatty acid elongase Baldspot/ELOVL6. In the absence of this enzyme, cells undergoing ER stress display reduced cell death, and degeneration in a Drosophila disease model. Feeding of excess fatty acids increases degeneration to original disease levels, linking the regulatory activity of Baldspot to its enzymatic activity. Finally, we demonstrate that Baldspot can alter the ER stress response under a variety of other ER stress conditions. Our studies demonstrate that Baldspot/ELOVL6 is a ubiquitous regulator of the ER stress response and is a good candidate therapeutic target.

scholarly journals Nickel Enhances Zinc-Induced Neuronal Cell Death by Priming the Endoplasmic Reticulum Stress Response

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Ken-ichiro Tanaka ◽  
Misato Kasai ◽  
Mikako Shimoda ◽  
Ayane Shimizu ◽  
Maho Kubota ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Stress Response ◽  
Trace Metals ◽  
Er Stress ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Endoplasmic Reticulum Stress Response ◽  
Dependent Manner ◽  
Er Stress Response

Trace metals such as zinc (Zn), copper (Cu), and nickel (Ni) play important roles in various physiological functions such as immunity, cell division, and protein synthesis in a wide variety of species. However, excessive amounts of these trace metals cause disorders in various tissues of the central nervous system, respiratory system, and other vital organs. Our previous analysis focusing on neurotoxicity resulting from interactions between Zn and Cu revealed that Cu2+ markedly enhances Zn2+-induced neuronal cell death by activating oxidative stress and the endoplasmic reticulum (ER) stress response. However, neurotoxicity arising from interactions between zinc and metals other than copper has not been examined. Thus, in the current study, we examined the effect of Ni2+ on Zn2+-induced neurotoxicity. Initially, we found that nontoxic concentrations (0–60 μM) of Ni2+ enhance Zn2+-induced neurotoxicity in an immortalized hypothalamic neuronal cell line (GT1-7) in a dose-dependent manner. Next, we analyzed the mechanism enhancing neuronal cell death, focusing on the ER stress response. Our results revealed that Ni2+ treatment significantly primed the Zn2+-induced ER stress response, especially expression of the CCAAT-enhancer-binding protein homologous protein (CHOP). Finally, we examined the effect of carnosine (an endogenous peptide) on Ni2+/Zn2+-induced neurotoxicity and found that carnosine attenuated Ni2+/Zn2+-induced neuronal cell death and ER stress occurring before cell death. Based on our results, Ni2+ treatment significantly enhances Zn2+-induced neuronal cell death by priming the ER stress response. Thus, compounds that decrease the ER stress response, such as carnosine, may be beneficial for neurological diseases.

scholarly journals Enhanced Lysosomal Activity Is Involved in Bax Inhibitor-1-induced Regulation of the Endoplasmic Reticulum (ER) Stress Response and Cell Death against ER Stress

2011 ◽  
Vol 286 (28) ◽  
pp. 24743-24753 ◽  
Author(s):  
Geum-Hwa Lee ◽  
Do-Sung Kim ◽  
Hyung-Tae Kim ◽  
Jung-Wook Lee ◽  
Chin-Ha Chung ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Stress Response ◽  
Er Stress ◽  
Lysosomal Activity ◽  
Er Stress Response

scholarly journals PRMT1 suppresses ATF4-mediated endoplasmic reticulum response in cardiomyocytes

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Myong-Ho Jeong ◽  
Hyeon-Ju Jeong ◽  
Byeong-Yun Ahn ◽  
Jung-Hoon Pyun ◽  
Ilmin Kwon ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Stress Response ◽  
Er Stress ◽  
Regulatory Mechanism ◽  
Critical Role ◽  
Mechanistic Study ◽  
Stress Signaling ◽  
Deficient Mutant ◽  
Er Stress Response

AbstractEndoplasmic reticulum (ER) stress signaling plays a critical role in the control of cell survival or death. Persistent ER stress activates proapoptotic pathway involving the ATF4/CHOP axis. Although accumulating evidences support its important contribution to cardiovascular diseases, but its mechanism is not well characterized. Here, we demonstrate a critical role for PRMT1 in the control of ER stress in cardiomyocytes. The inhibition of PRMT1 augments tunicamycin (TN)-triggered ER stress response in cardiomyocytes while PRMT1 overexpression attenuates it. Consistently, PRMT1 null hearts show exacerbated ER stress and cell death in response to TN treatment. Interestingly, ATF4 depletion attenuates the ER stress response induced by PRMT1 inhibition. The methylation-deficient mutant of ATF4 with the switch of arginine 239 to lysine exacerbates ER stress accompanied by enhanced levels of proapoptotic cleaved Caspase3 and phosphorylated-γH2AX in response to TN. The mechanistic study shows that PRMT1 modulates the protein stability of ATF4 through methylation. Taken together, our data suggest that ATF4 methylation on arginine 239 by PRMT1 is a novel regulatory mechanism for protection of cardiomyocytes from ER stress-induced cell death.

Abstract 454: Endoplasmic Reticulum Stress Response in Pressure-Overloaded Ischemic-Reperfused Hearts

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Mahmood Mozaffari ◽  
Jun Yao Liu ◽  
Babak Baban
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Stress Response ◽  
Er Stress ◽  
Inflammatory Cytokine ◽  
Ischemia Reperfusion ◽  
Pressure Overload ◽  
Annexin V ◽  
Endoplasmic Reticulum Stress Response ◽  
Er Stress Response

An integral component of endoplasmic reticulum (ER) stress-induced apoptosis is expression of growth arrest- and DNA damage inducible protein 153 (GADD153); this protein is normally expressed in low levels but its expression markedly increases following sustained stress to the ER. GADD153 regulates both apoptosis and inflammatory response. We previously showed that pressure overload exacerbates myocardial ischemia reperfusion (IR) injury. In this study, we tested the hypothesis that pressure overload regulates ER stress response manifested as increased GADD153 expression thereby upregulating inflammatory cytokine production and contributing to worsening of myocardial IR injury. Accordingly, Langendorff-perfused rat hearts were subjected to global IR protocol with perfusion pressure set at 80 or 160 cmH 2 O; normoxic hearts served as controls. Compared to normoxia, an IR insult increased expressions of pro-inflammatory cytokine (interleukin (IL)-17) and GADD153 in association with increased cell death. In the ischemic-reperfused hearts, pressure overload a) increased expression of GADD153, b) reduced interleukin (IL)-10 but increased IL-17 and c) increased annexin V immunostaining as well as apoptotic and necrotic cell death. Collectively, the results suggest that pressure overload exacerbates cell death in the isolated ischemic-reperfused heart involving regulation of ER stress response and inflammation.

Inhibition of Autophagy Promotes Bortezomib-Mediated Cell Death in Myeloma Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3677-3677 ◽  
Author(s):  
Terry H. Landowski ◽  
Aluvia M Escalante ◽  
Andrew Jefferson ◽  
Robert T Dorr ◽  
Ronald Lynch
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Stress Response ◽  
Er Stress ◽  
B Cell ◽  
Cellular Stress Response ◽  
Calpain Activity ◽  
B Cell Malignancies ◽  
Myeloma Cells ◽  
Er Stress Response

Abstract The 26S proteasome is a key regulator of proteins controlling many important cellular functions, including cell cycle progression, differentiation, gene transcription and apoptosis. Proteasome inhibition is a new therapeutic strategy that has shown promise in the treatment of B cell malignancies, primarily multiple myeloma. We and others have demonstrated that proteasome inhibitors induce endoplasmic reticulum (ER) stress and activate an unfolded protein response (UPR) in transformed cells. Our previous work demonstrated that bortezomib induces an endoplasmic reticulum (ER) stress response ultimately leading to calcium-dependent apoptotic cell death. Co-treatment of myeloma cells with the mitochondrial uniporter inhibitor ruthenium red (RuR) abrogated bortezomib mediated cell death, indicating that the cytotoxic effects of proteasomal inhibition requires dysregulation of intracellular Ca2+. Intracellular Ca2+ has also been implicated in the cellular stress response known as autophagy or “self-eating”. Macroautophagy (hereafter referred to as autophagy) is induced by various cellular stresses including nutrient deprivation, metabolic insufficiency, interruption of growth factor signaling, elevated ROS, accumulation of intracellular Ca2+, and the UPR. The biochemical events linking the cellular stress response with the induction of autophagy, and the relationship between autophagy and apoptosis is not well understood. In this study, we investigate the role of the Ca2+ dependent serine protease, calpain, as a mediator of the conversion from autophagic cell survival to accelerated cell death in the ER stress response. We demonstrate that the proteasome inhibitor, bortezomib, initiates autophagy in myeloma cells, and protection from bortezomib-mediated cell death by mitochondrial Ca2+ inhibitors is associated with a promotion and stabilization of the autophagosome. This response can be reversed, and indeed, accelerated, leading to enhanced cell death, by blockade of calpain activity. Inhibition of calpain activity with the tri-peptide zLLY-FMK (Calpain Inhibitor IV, (CiIV) or the non-peptide inhibitor, PD150606, demonstrated a significant increase in the cytotoxic activity of bortezomib. Similarly, elimination of the small catalytic subunit, CAPNS1, using siRNA, enhanced bortezomib-mediated cell death, and prevented autophagosome-lysosomal progression. Furthermore, inhibition of calpain by clinically approved HIV protease inhibitors including Nelfinavir, Ritonavir, Saquinavir, and Indinavir sulfate, significantly increased the cytotoxic activity of bortezomib in vitro. We suggest that disregulation of Ca2+ by bortezomib-mediated ER stress activates the autophagic survival response. Inhibition of mitochondrial Ca2+ uptake by the uniporter inhibitor RuR promotes autophagy, and confers resistance to bortezomib. Conversely, inhibition of the Ca2+-dependent serine protease, calpain, prevents autophagolysosome maturation, and subverts the survival response to cell death. These data are likely to have important clinical implications for the treatment of refractory myeloma and other B cell malignancies.

scholarly journals Differential regulation of the endoplasmic reticulum stress response in pancreatic β-cells exposed to long-chain saturated and monounsaturated fatty acids

2008 ◽  
Vol 197 (3) ◽  
pp. 553-563 ◽  
Author(s):  
Eleftheria Diakogiannaki ◽  
Hannah J Welters ◽  
Noel G Morgan
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Initiation Factor ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Er Stress Response ◽  
Stress Pathway ◽  
Long Chain

Exposure of pancreatic β-cells to long-chain fatty acids leads to the activation of some components of the endoplasmic reticulum (ER) stress pathway and this mechanism may underlie the ability of certain fatty acids to promote β-cell death. We have studied ER stress in BRIN-BD11 β-cells exposed to either the saturated fatty acid palmitate (C16:0) or the monounsaturated palmitoleate (C16:1). Palmitate (0.025–0.25 mM) induced the expression of various markers of the RNA-dependent protein kinase-like ER eukaryotic initiation factor 2α (eIF2α) kinase (PERK)-dependent pathway of ER stress (phospho-eIF2α; ATF4, activating transcription factor 4 and C/EBP homologous protein (CHOP-10)) although it failed to promote the expression of the ER chaperone GRP78. By contrast, palmitoleate did not induce any markers of the ER stress pathway even at concentrations as high as 1 mM. When palmitate and palmitoleate were added in combination, a marked attenuation of the ER stress response occurred. Under these conditions, the levels of phospho-eIF2α, ATF4 and CHOP-10 were reduced to less than those found in control cells. Palmitoleate also attenuated the ER stress response to the protein glycosylation inhibitor, tunicamycin, and improved the viability of the cells exposed to this agent. Exposure of the BRIN-BD11 cells to the protein phosphatase inhibitor, salubrinal, in the absence of fatty acids resulted in increased eIF2α phosphorylation but this was abolished by co-incubation with palmitoleate. We conclude that saturated fatty acids activate components of the PERK-dependent ER stress pathway in β-cells, ultimately leading to increased apoptosis. This effect is antagonised by monounsaturates that may exert their anti-apoptotic actions by regulating the activity of one or more kinase enzymes involved in mediating the phosphorylation of eIF2α.

scholarly journals Two Italian Patients with ELOVL4-Related Neuro-Ichthyosis:  Expanding the Genotypic and Phenotypic Spectrum and Ultrastructural Characterization

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 343
Author(s):  
Andrea Diociaiuti ◽  
Diego Martinelli ◽  
Francesco Nicita ◽  
Claudia Cesario ◽  
Elisa Pisaneschi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Chain Fatty Acid ◽  
Spinocerebellar Ataxia Type ◽  
Facial Dysmorphism ◽  
Macular Dystrophy ◽  
Compound Heterozygous ◽  
Long Chain Fatty Acid ◽  
Fatty Acid Elongase ◽  
Spastic Quadriplegia ◽  
Long Chain

Elongation of Very Long Chain Fatty Acid-4 (ELOVL4) is a fatty acid elongase responsible for very long-chain fatty acid biosynthesis in the brain, retina, and skin. Heterozygous mutations in ELOVL4 gene cause Stargardt-like macular dystrophy and spinocerebellar ataxia type-34, while different homozygous mutations have been associated with ichthyosis, spastic quadriplegia, and mental retardation syndrome in three kindred. We report the first two Italian children affected with neuro-ichthyosis due to the previously undescribed ELOVL4 homozygous frameshift variant c.435dupT (p.Ile146TyrfsTer29), and compound heterozygous variants c.208C>T (p.Arg70Ter) and c.487T>C (p.Cys163Arg), respectively. Both patients were born with collodion membrane followed by development of diffuse mild hyperkeratosis and scaling, localized erythema, and palmoplantar keratoderma. One infant displayed mild facial dysmorphism. They suffered from failure to thrive, and severe gastro-esophageal reflux with pulmonary aspiration. The patients presented axial hypotonia, hypertonia of limbs, and absent head control with poor eye contact from infancy. Visual evoked potentials showed markedly increased latency and poor morphological definition, indicative of alteration of the retro-retinal visual pathways in both patients. Ultrastructural skin examination revealed abnormalities of lamellar bodies with altered release in the epidermal granular and horny layer intracellular spaces. Our findings contribute to expanding the phenotypic and genotypic features of ELOVL4-related neuro-ichthyosis.

scholarly journals The dynamic effect of regulatory genetic variation on the in vivo ER stress transcriptional response

2021 ◽  
Author(s):  
Nikki D. Russell ◽  
Clement Y. Chow
Keyword(s):  
Genetic Variation ◽  
Stress Response ◽  
Er Stress ◽  
Transcriptional Response ◽  
Mouse Strains ◽  
Transcriptional Responses ◽  
Er Stress Response ◽  
Multiple Environments ◽  
Context Specific

AbstractGenotype x Environment (GxE) interactions occur when environmental conditions drastically change the effect of a genetic variant. In order to truly understand the effect of genetic variation, we need to incorporate multiple environments into our analyses. Many variants, under steady state conditions, may be silent or even have the opposite effect under stress conditions. This study uses an in vivo mouse model to investigate how the effect of genetic variation changes with tissue type and cellular stress. Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the ER. This triggers the unfolded protein response (UPR), a large transcriptional response which attempts to return the cell to homeostasis. This transcriptional response, despite being a well conserved, basic cellular process, is highly variable across different genetic backgrounds, making it an ideal system to study GxE effects. In this study, we sought to better understand how genetic variation alters expression across tissues, in the presence and absence of ER stress. The use of different mouse strains and their F1s allow us to also identify context specific cis- and trans-regulatory mechanisms underlying variable transcriptional responses. We found hundreds of genes that respond to ER stress in a tissue- and/or genotype-dependent manner. Genotype-dependent ER stress-responsive genes are enriched for processes such as protein folding, apoptosis, and protein transport, indicating that some of the variability occurs in canonical ER stress factors. The majority of regulatory mechanisms underlying these variable transcriptional responses derive from cis-regulatory variation and are unique to a given tissue or ER stress state. This study demonstrates the need for incorporating multiple environments in future studies to better elucidate the effect of any particular genetic factor in basic biological pathways, like the ER stress response.Author SummaryThe effect of genetic variation is dependent on environmental context. Here we use genetically diverse mouse strains to understand how genetic variation interacts with stress state to produce variable transcriptional profiles. In this study, we take advantage of the endoplasmic reticulum (ER) stress response which is a large transcriptional response to misfolded proteins. Using this system, we uncovered tissue- and ER stress-specific effects of genetic variation on gene expression. Genes with genotype-dependent variable expression levels in response to ER stress were enriched for canonical ER stress functions, such as protein folding and transport. These variable effects of genetic variation are driven by unique sets of regulatory variation that are only active under context-specific circumstances. The results of this study highlight the importance of including multiple environments and genetic backgrounds when studying the ER stress response and other cellular pathways.

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