scholarly journals An inducible ER–Golgi tether facilitates ceramide transport to alleviate lipotoxicity

2016 ◽  
Vol 216 (1) ◽  
pp. 131-147 ◽  
Author(s):  
Li-Ka Liu ◽  
Vineet Choudhary ◽  
Alexandre Toulmay ◽  
William A. Prinz
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Golgi Complex ◽  
Growth Arrest ◽  
Signaling Molecules ◽  
Yeast Protein ◽  
Response To Stress ◽  
Sphingolipid Biosynthesis ◽  
Complex Sphingolipids ◽  
Close Contacts

Ceramides are key intermediates in sphingolipid biosynthesis and potent signaling molecules. However, excess ceramide is toxic, causing growth arrest and apoptosis. In this study, we identify a novel mechanism by which cells prevent the toxic accumulation of ceramides; they facilitate nonvesicular ceramide transfer from the endoplasmic reticulum (ER) to the Golgi complex, where ceramides are converted to complex sphingolipids. We find that the yeast protein Nvj2p promotes the nonvesicular transfer of ceramides from the ER to the Golgi complex. The protein is a tether that generates close contacts between these compartments and may directly transport ceramide. Nvj2p normally resides at contacts between the ER and other organelles, but during ER stress, it relocalizes to and increases ER–Golgi contacts. ER–Golgi contacts fail to form during ER stress in cells lacking Nvj2p. Our findings demonstrate that cells regulate ER–Golgi contacts in response to stress and reveal that nonvesicular ceramide transfer out of the ER prevents the buildup of toxic amounts of ceramides.

scholarly journals Target of rapamycin signaling mediates vacuolar fission caused by endoplasmic reticulum stress in Saccharomyces cerevisiae

2015 ◽  
Vol 26 (25) ◽  
pp. 4618-4630 ◽  
Author(s):  
Bobbiejane Stauffer ◽  
Ted Powers
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Intracellular Localization ◽  
Downstream Effectors ◽  
Genome Wide ◽  
Genetic Perturbations ◽  
Response To Stress ◽  
Induced Changes ◽  
Yeast Mutants

The yeast vacuole is equivalent to the mammalian lysosome and, in response to diverse physiological and environmental stimuli, undergoes alterations both in size and number. Here we demonstrate that vacuoles fragment in response to stress within the endoplasmic reticulum (ER) caused by chemical or genetic perturbations. We establish that this response does not involve known signaling pathways linked previously to ER stress but instead requires the rapamycin-sensitive TOR Complex 1 (TORC1), a master regulator of cell growth, together with its downstream effectors, Tap42/Sit4 and Sch9. To identify additional factors required for ER stress–induced vacuolar fragmentation, we conducted a high-throughput, genome-wide visual screen for yeast mutants that are refractory to ER stress–induced changes in vacuolar morphology. We identified several genes shown previously to be required for vacuolar fusion and/or fission, validating the utility of this approach. We also identified a number of new components important for fragmentation, including a set of proteins involved in assembly of the V-ATPase. Remarkably, we find that one of these, Vph2, undergoes a change in intracellular localization in response to ER stress and, moreover, in a manner that requires TORC1 activity. Together these results reveal a new role for TORC1 in the regulation of vacuolar behavior.

scholarly journals Endoplasmic reticulum stress response in yeast and humans

2014 ◽  
Vol 34 (4) ◽  
Author(s):  
Haoxi Wu ◽  
Benjamin S. H. Ng ◽  
Guillaume Thibault
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Structures ◽  
Signal Transduction Pathway ◽  
Yeast Cells ◽  
Endoplasmic Reticulum Stress Response ◽  
Unfolded Protein ◽  
Intracellular Signal Transduction Pathway ◽  
Response To Stress ◽  
Protein Response

Stress pathways monitor intracellular systems and deploy a range of regulatory mechanisms in response to stress. One of the best-characterized pathways, the UPR (unfolded protein response), is an intracellular signal transduction pathway that monitors ER (endoplasmic reticulum) homoeostasis. Its activation is required to alleviate the effects of ER stress and is highly conserved from yeast to human. Although metazoans have three UPR outputs, yeast cells rely exclusively on the Ire1 (inositol-requiring enzyme-1) pathway, which is conserved in all Eukaryotes. In general, the UPR program activates hundreds of genes to alleviate ER stress but it can lead to apoptosis if the system fails to restore homoeostasis. In this review, we summarize the major advances in understanding the response to ER stress in Sc (Saccharomyces cerevisiae), Sp (Schizosaccharomyces pombe) and humans. The contribution of solved protein structures to a better understanding of the UPR pathway is discussed. Finally, we cover the interplay of ER stress in the development of diseases.

scholarly journals Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153).

1996 ◽  
Vol 16 (8) ◽  
pp. 4273-4280 ◽  
Author(s):  
X Z Wang ◽  
B Lawson ◽  
J W Brewer ◽  
H Zinszner ◽  
A Sanjay ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Uv Light ◽  
Growth Arrest ◽  
Protein Glycosylation ◽  
Temperature Sensitive ◽  
Gene Encoding ◽  
Homologous Protein

The gene encoding C/EBP-homologous protein (CHOP), also known as growth arrest and DNA-damage-inducible gene 153 (GADD153), is activated by agents that adversely affect the function of the endoplasmic reticulum (ER). Because of the pleiotropic effects of such agents on other cellular processes, the role of ER stress in inducing CHOP gene expression has remained unclear. We find that cells with conditional (temperature-sensitive) defects in protein glycosylation (CHO K12 and BHK tsBN7) induce CHOP when cultured at the nonpermissive temperature. In addition, cells that are defective in initiating the ER stress response, because of overexpression of an exogenous ER chaperone, BiP/GRP78, exhibit attenuated inducibility of CHOP. Surprisingly, attenuated induction of CHOP was also noted in BiP-overexpressing cells treated with methyl methanesulfonate, an agent thought to activate CHOP by causing DNA damage. The roles of DNA damage and growth arrest in the induction of CHOP were therefore reexamined. Induction of growth arrest by culture to confluence or treatment with the enzymatic inhibitor N-(phosphonacetyl)-L-aspartate did not induce CHOP. Furthermore, both a DNA-damage-causing nucleoside analog (5-hydroxymethyl-2'-deoxyuridine) and UV light alone did not induce CHOP. These results suggest that CHOP is more responsive to ER stress than to growth arrest or DNA damage and indicate a potential role for CHOP in linking stress in the ER to alterations in gene expression.

Homocysteine-Induced Endoplasmic Reticulum Stress and Growth Arrest Leads to Specific Changes in Gene Expression in Human Vascular Endothelial Cells

Blood ◽  
1999 ◽  
Vol 94 (3) ◽  
pp. 959-967 ◽  
Author(s):  
P. Andrew Outinen ◽  
Sudesh K. Sood ◽  
Sabine I. Pfeifer ◽  
Sushmita Pamidi ◽  
Thomas J. Podor ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Umbilical Vein ◽  
Expression Profiles ◽  
Growth Arrest ◽  
Cdna Microarrays ◽  
Northern Blotting ◽  
Early Event

Alterations in the cellular redox potential by homocysteine promote endothelial cell (EC) dysfunction, an early event in the progression of atherothrombotic disease. In this study, we demonstrate that homocysteine causes endoplasmic reticulum (ER) stress and growth arrest in human umbilical vein endothelial cells (HUVEC). To determine if these effects reflect specific changes in gene expression, cDNA microarrays were screened using radiolabeled cDNA probes generated from mRNA derived from HUVEC, cultured in the absence or presence of homocysteine. Good correlation was observed between expression profiles determined by this method and by Northern blotting. Consistent with its adverse effects on the ER, homocysteine alters the expression of genes sensitive to ER stress (ie, GADD45, GADD153, ATF-4, YY1). Several other genes observed to be differentially expressed by homocysteine are known to mediate cell growth and differentiation (ie, GADD45, GADD153, Id-1, cyclin D1, FRA-2), a finding that supports the observation that homocysteine causes a dose-dependent decrease in DNA synthesis in HUVEC. Additional gene profiles also show that homocysteine decreases cellular antioxidant potential (glutathione peroxidase, NKEF-B PAG, superoxide dismutase, clusterin), which could potentially enhance the cytotoxic effects of agents or conditions known to cause oxidative damage. These results successfully demonstrate the use of cDNA microarrays in identifying homocysteine-respondent genes and indicate that homocysteine-induced ER stress and growth arrest reflect specific changes in gene expression in human vascular EC.

scholarly journals Comparison of mRNA localization and regulation during endoplasmic reticulum stress in Drosophila cells

2013 ◽  
Vol 24 (1) ◽  
pp. 14-20 ◽  
Author(s):  
Deepika Gaddam ◽  
Nicole Stevens ◽  
Julie Hollien
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Transmembrane Protein ◽  
Nuclease Activity ◽  
Mrna Degradation ◽  
Dependent Manner ◽  
Drosophila S2 Cells ◽  
Er Targeting ◽  
Response To Stress ◽  
Drosophila Cells

Ire1 is an endoplasmic reticulum (ER) transmembrane protein that senses disturbances in protein folding homeostasis and contributes to a multifaceted response to stress. The nuclease activity of Ire1, in addition to splicing the mRNA encoding the transcription factor Xbp1, mediates mRNA degradation in response to ER stress through a pathway termed regulated Ire1-dependent decay (RIDD). We previously showed that ER targeting of substrates is necessary for RIDD; in this paper, we show that ER localization is also sufficient to induce decay in a normally unaffected mRNA. Using microarrays, we also measured relative mRNA degradation in the presence and absence of ER stress in Drosophila S2 cells, and determined mRNA membrane association using detergent fractionation. The vast majority of mRNAs that were strongly associated with the ER were degraded faster during ER stress in an Ire1-dependent manner, suggesting that RIDD is the default pathway for ER-localized mRNAs during stress. We also show that the mRNA encoding plexin A remains highly polysome associated during stress and escapes degradation by RIDD, and that its 5′ untranslated region can protect a strong RIDD target from degradation. These results suggest that while translation is generally attenuated during ER stress, continued translation of certain messages can protect them from degradation by RIDD.

scholarly journals Sphingolipids activate the endoplasmic reticulum stress surveillance pathway

2018 ◽  
Vol 217 (2) ◽  
pp. 495-505 ◽  
Author(s):  
Francisco Piña ◽  
Fumi Yagisawa ◽  
Keisuke Obara ◽  
J.D. Gregerson ◽  
Akio Kihara ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Daughter Cell ◽  
Yeast Saccharomyces Cerevisiae ◽  
Daughter Cells ◽  
Stressed Cells ◽  
Aureobasidin A ◽  
Lines Of Evidence ◽  
Complex Sphingolipids

Proper inheritance of functional organelles is vital to cell survival. In the budding yeast, Saccharomyces cerevisiae, the endoplasmic reticulum (ER) stress surveillance (ERSU) pathway ensures that daughter cells inherit a functional ER. Here, we show that the ERSU pathway is activated by phytosphingosine (PHS), an early biosynthetic sphingolipid. Multiple lines of evidence support this: (1) Reducing PHS levels with myriocin diminishes the ability of cells to induce ERSU phenotypes. (2) Aureobasidin A treatment, which blocks conversion of early intermediates to downstream complex sphingolipids, induces ERSU. (3) orm1Δorm2Δ cells, which up-regulate PHS, show an ERSU response even in the absence of ER stress. (4) Lipid analyses confirm that PHS levels are indeed elevated in ER-stressed cells. (5) Lastly, the addition of exogenous PHS is sufficient to induce all ERSU phenotypes. We propose that ER stress elevates PHS, which in turn activates the ERSU pathway to ensure future daughter-cell viability.

scholarly journals CCL23 in Balancing the Act of Endoplasmic Reticulum Stress and Antitumor Immunity in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Dev Karan
Keyword(s):  
Hepatocellular Carcinoma ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Antitumor Immunity ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Functional Activities ◽  
Chemotherapy Drugs ◽  
Response To Stress ◽  
Stress Influences

Endoplasmic reticulum (ER) stress is a cellular process in response to stress stimuli in protecting functional activities. However, sustained hyperactive ER stress influences tumor growth and development. Hepatocytes are enriched with ER and highly susceptible to ER perturbations and stress, which contribute to immunosuppression and the development of aggressive and drug-resistant hepatocellular carcinoma (HCC). ER stress-induced inflammation and tumor-derived chemokines influence the immune cell composition at the tumor site. Consequently, a decrease in the CCL23 chemokine in hepatic tumors is associated with poor survival of HCC patients and could be a mechanism hepatic tumor cells use to evade the immune system. This article describes the prospective role of CCL23 in alleviating ER stress and its impact on the HCC tumor microenvironment in promoting antitumor immunity. Moreover, approaches to reactivate CCL23 combined with immune checkpoint blockade or chemotherapy drugs may provide novel opportunities to target hepatocellular carcinoma.

Organisation in the Structure of the Cytoplasmic Ground Substance

1978 ◽  
Vol 36 (3) ◽  
pp. 627-639
Author(s):  
K.R. Porter
Keyword(s):  
Endoplasmic Reticulum ◽  
Golgi Complex ◽  
Random Distribution ◽  
Ground Substance ◽  
The Matrix ◽  
Cell Processes ◽  
Cytoplasmic Ground Substance

Most types of cells are known from their structure and overall form to possess a characteristic organization. In some instances this is evident in the non-random disposition of organelles and such system subunits as cisternae of the endoplasmic reticulum or the Golgi complex. In others it appears in the distribution and orientation of cytoplasmic fibrils. And in yet others the organization finds expression in the non-random distribution and orientation of microtubules, especially as found in highly anisometric cells and cell processes. The impression is unavoidable that in none of these cases is the organization achieved without the involvement of the cytoplasmic ground substance (CGS) or matrix. This impression is based on the fact that a matrix is present and that in all instances these formed structures, whether membranelimited or filamentous, are suspended in it. In some well-known instances, as in arrays of microtubules which make up axonemes and axostyles, the matrix resolves itself into bridges (and spokes) between the microtubules, bridges which are in some cases very regularly disposed and uniform in size (Mcintosh, 1973; Bloodgood and Miller, 1974; Warner and Satir, 1974).

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