Endoplasmic reticulum stress signal impairs erythropoietin production: a role for ATF4

2013 ◽  
Vol 304 (4) ◽  
pp. C342-C353 ◽  
Author(s):  
Chih-Kang Chiang ◽  
Masaomi Nangaku ◽  
Tetsuhiro Tanaka ◽  
Takao Iwawaki ◽  
Reiko Inagi
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Enhancer Activity ◽  
Unfolded Protein ◽  
Stress Signal ◽  
Liver And Kidney ◽  
Activating Transcription Factor

Hypoxia upregulates the hypoxia-inducible factor (HIF) pathway and the endoplasmic reticulum (ER) stress signal, unfolded protein response (UPR). The cross talk of both signals affects the pathogenic alteration by hypoxia. Here we showed that ER stress induced by tunicamycin or thapsigargin suppressed inducible (CoCl2or hypoxia) transcription of erythropoietin (EPO), a representative HIF target gene, in HepG2. This suppression was inversely correlated with UPR activation, as estimated by expression of the UPR regulator glucose-regulated protein 78, and restored by an ER stress inhibitor, salubrinal, in association with normalization of the UPR state. Importantly, the decreased EPO expression was also observed in HepG2 overexpressing UPR activating transcription factor (ATF)4. Overexpression of mutated ATF4 that lacks the transcriptional activity did not alter EPO transcriptional regulation. Transcriptional activity of the EPO 3′-enhancer, which is mainly regulated by HIF, was abolished by both ER stressors and ATF4 overexpression, while nuclear HIF accumulation or expression of other HIF target genes was not suppressed by ER stress. Chromatin immunoprecipitation analysis identified a novel ATF4 binding site (TGACCTCT) within the EPO 3′-enhancer region, suggesting a distinct role for ATF4 in UPR-dependent suppression of the enhancer. Induction of ER stress in rat liver and kidney by tunicamycin decreased the hepatic and renal mRNA and plasma level of EPO. Collectively, ER stress selectively impairs the transcriptional activity of EPO but not of other HIF target genes. This effect is mediated by suppression of EPO 3′-enhancer activity via ATF4 without any direct effect on HIF, indicating that UPR contributes to oxygen-sensing regulation of EPO.

scholarly journals Unification of Opposites between Two Antioxidant Transcription Factors Nrf1 and Nrf2 in Mediating Distinct Cellular Responses to the Endoplasmic Reticulum Stressor Tunicamycin

Antioxidants ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 4 ◽  
Author(s):  
Yu-ping Zhu ◽  
Ze Zheng ◽  
Shaofan Hu ◽  
Xufang Ru ◽  
Zhuo Fan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Er Stress ◽  
Target Genes ◽  
Cellular Responses ◽  
Water Soluble ◽  
Heme Oxygenase 1 ◽  
Nuclear Factor ◽  
Activating Transcription Factor

The water-soluble Nrf2 (nuclear factor, erythroid 2-like 2, also called Nfe2l2) is accepted as a master regulator of antioxidant responses to cellular stress, and it was also identified as a direct target of the endoplasmic reticulum (ER)-anchored PERK (protein kinase RNA-like endoplasmic reticulum kinase). However, the membrane-bound Nrf1 (nuclear factor, erythroid 2-like 1, also called Nfe2l1) response to ER stress remains elusive. Herein, we report a unity of opposites between these two antioxidant transcription factors, Nrf1 and Nrf2, in coordinating distinct cellular responses to the ER stressor tunicamycin (TU). The TU-inducible transcription of Nrf1 and Nrf2, as well as GCLM (glutamate cysteine ligase modifier subunit) and HO-1 (heme oxygenase 1), was accompanied by activation of ER stress signaling networks. Notably, the unfolded protein response (UPR) mediated by ATF6 (activating transcription factor 6), IRE1 (inositol requiring enzyme 1) and PERK was significantly suppressed by Nrf1α-specific knockout, but hyper-expression of Nrf2 and its target genes GCLM and HO-1 has retained in Nrf1α−/− cells. By contrast, Nrf2−/−ΔTA cells with genomic deletion of its transactivation (TA) domain resulted in significant decreases of GCLM, HO-1 and Nrf1; this was accompanied by partial decreases of IRE1 and ATF6, rather than PERK, but with an increase of ATF4 (activating transcription factor 4). Interestingly, Nrf1 glycosylation and its trans-activity to mediate the transcriptional expression of the 26S proteasomal subunits, were repressed by TU. This inhibitory effect was enhanced by Nrf1α−/− and Nrf2−/−ΔTA, but not by a constitutive activator caNrf2ΔN (that increased abundances of the non-glycosylated and processed Nrf1). Furthermore, caNrf2ΔN also enhanced induction of PERK and IRE1 by TU, but reduced expression of ATF4 and HO-1. Thus, it is inferred that such distinct roles of Nrf1 and Nrf2 are unified to maintain cell homeostasis by a series of coordinated ER-to-nuclear signaling responses to TU. Nrf1α (i.e., a full-length form) acts in a cell-autonomous manner to determine the transcription of most of UPR-target genes, albeit Nrf2 is also partially involved in this process. Consistently, transactivation of ARE (antioxidant response element)-driven BIP (binding immunoglobulin protein)-, PERK- and XBP1 (X-box binding protein 1)-Luc reporter genes was mediated directly by Nrf1 and/or Nrf2. Interestingly, Nrf1α is more potent than Nrf2 at mediating the cytoprotective responses against the cytotoxicity of TU alone or plus tBHQ (tert-butylhydroquinone). This is also further supported by the evidence that the intracellular reactive oxygen species (ROS) levels are increased in Nrf1α−/− cells, but rather are, to our surprise, decreased in Nrf2−/−ΔTA cells.

scholarly journals Endoplasmic reticulum stress regulation of the Kar2p/BiP chaperone alleviates proteotoxicity via dual degradation pathways

2012 ◽  
Vol 23 (4) ◽  
pp. 630-641 ◽  
Author(s):  
Chia-Ling Hsu ◽  
Rupali Prasad ◽  
Christie Blackman ◽  
Davis T. W. Ng
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Target Genes ◽  
Regulatory Element ◽  
Unfolded Protein ◽  
Single Target ◽  
Transcriptional Regulatory ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Stress Activation

The unfolded protein response (UPR) monitors and maintains protein homeostasis in the endoplasmic reticulum (ER). In budding yeast, the UPR is a transcriptional regulatory pathway that is quiescent under normal conditions. Under conditions of acute ER stress, activation of UPR targets is essential for cell viability. How individual target genes contribute to stress tolerance is unclear. Uncovering these roles is hampered because most targets also play important functions in the absence of stress. To differentiate stress-specific roles from everyday functions, a single target gene was uncoupled from UPR control by eliminating its UPR-specific regulatory element. Through this approach, the UPR remains intact, aside from its inability to induce the designated target. Applying the strategy to the major ER chaperone Kar2p/BiP revealed the physiological function of increasing its cellular concentration. Despite hundreds of target genes under UPR control, we show that activation of KAR2 is indispensable to alleviate some forms of ER stress. Specifically, activation is essential to dispose misfolded proteins that are otherwise toxic. Surprisingly, induced BiP/Kar2p molecules are dedicated to alleviating stress. The inability to induce KAR2 under stress had no effect on its known housekeeping functions.

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 Specificity in endoplasmic reticulum-stress signaling in yeast entails a step-wise engagement of HAC1 mRNA to clusters of the stress sensor Ire1

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Eelco van Anken ◽  
David Pincus ◽  
Scott Coyle ◽  
Tomás Aragón ◽  
Christof Osman ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Target Genes ◽  
Transmembrane Domain ◽  
Transcription Activator ◽  
Stress Sensor ◽  
Unfolded Protein ◽  
Oligomeric Assembly ◽  
The Unfolded Protein Response ◽  
Linker Domain

Insufficient protein-folding capacity in the endoplasmic reticulum (ER) induces the unfolded protein response (UPR). In the ER lumen, accumulation of unfolded proteins activates the transmembrane ER-stress sensor Ire1 and drives its oligomerization. In the cytosol, Ire1 recruits HAC1 mRNA, mediating its non-conventional splicing. The spliced mRNA is translated into Hac1, the key transcription activator of UPR target genes that mitigate ER-stress. In this study, we report that oligomeric assembly of the ER-lumenal domain is sufficient to drive Ire1 clustering. Clustering facilitates Ire1's cytosolic oligomeric assembly and HAC1 mRNA docking onto a positively charged motif in Ire1's cytosolic linker domain that tethers the kinase/RNase to the transmembrane domain. By the use of a synthetic bypass, we demonstrate that mRNA docking per se is a pre-requisite for initiating Ire1's RNase activity and, hence, splicing. We posit that such step-wise engagement between Ire1 and its mRNA substrate contributes to selectivity and efficiency in UPR signaling.

scholarly journals Distinct roles of activating transcription factor 6 (ATF6) and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase (PERK) in transcription during the mammalian unfolded protein response

2002 ◽  
Vol 366 (2) ◽  
pp. 585-594 ◽  
Author(s):  
Tetsuya OKADA ◽  
Hiderou YOSHIDA ◽  
Rieko AKAZAWA ◽  
Manabu NEGISHI ◽  
Kazutoshi MORI
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Protein Kinase ◽  
Er Stress ◽  
Double Stranded Rna ◽  
Unfolded Protein ◽  
Genes Encoding ◽  
Membrane Bound ◽  
Activating Transcription Factor ◽  
Protein Response

In response to accumulation of unfolded proteins in the endoplasmic reticulum (ER), a homoeostatic response, termed the unfolded protein response (UPR), is activated in all eukaryotic cells. The UPR involves only transcriptional regulation in yeast, and approx. 6% of all yeast genes, encoding not only proteins to augment the folding capacity in the ER, but also proteins working at various stages of secretion, are induced by ER stress [Travers, Patil, Wodicka, Lockhart, Weissman and Walter (2000) Cell (Cambridge, Mass.) 101, 249–258]. In the present study, we conducted microarray analysis of HeLa cells, although our analysis covered only a small fraction of the human genome. A great majority of human ER stress-inducible genes (approx. 1% of 1800 genes examined) were classified into two groups. One group consisted of genes encoding ER-resident molecular chaperones and folding enzymes, and these genes were directly regulated by the ER-membrane-bound transcription factor activating transcription factor (ATF) 6. The ER-membrane-bound protein kinase double-stranded RNA-activated protein kinase-like ER kinase (PERK)-mediated signalling pathway appeared to be responsible for induction of the remaining genes, which are not involved in secretion, but may be important after cellular recovery from ER stress. In higher eukaryotes, the PERK-mediated translational-attenuation system is known to operate in concert with the transcriptional-induction system. Thus we propose that mammalian cells have evolved a strategy to cope with ER stress different from that of yeast cells.

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.

Endoplasmic reticulum stress signaling: the microRNA connection

2013 ◽  
Vol 304 (12) ◽  
pp. C1117-C1126 ◽  
Author(s):  
Marion Maurel ◽  
Eric Chevet
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Small Noncoding Rnas ◽  
Unfolded Protein ◽  
Transcriptional Reprogramming ◽  
Stress Sensors ◽  
Activating Transcription Factor ◽  
Stress Dependent ◽  
Protein Response ◽  
Er Homeostasis

The endoplasmic reticulum (ER)-induced unfolded protein response (ERUPR) is an adaptive mechanism that is activated upon accumulation of misfolded proteins in the ER and aims at restoring ER homeostasis. The ERUPR is transduced by three major ER-resident stress sensors, namely PKR-like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6), and inositol requiring enzyme 1 (IRE1). Activation of these ER stress sensors leads to transcriptional reprogramming of the cells. Recently, microRNAs (miRNAs), small noncoding RNAs that generally repress gene expression, have emerged as key regulators of ER homeostasis and important players in ERUPR-dependent signaling. Moreover, the miRNAs biogenesis machinery appears to also be regulated upon ER stress. Herein we extensively review the relationships existing between “canonical” ERUPR signaling, control of ER homeostasis, and miRNAs. We reveal an intricate signaling network that might confer specificity and selectivity to the ERUPR in tissue- or stress-dependent fashion. We discuss these issues in the context of the physiological and pathophysiological roles of ERUPR signaling.

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.

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