Endoplasmic reticulum stress exacerbates inflammation in chronic rhinosinusitis with nasal polyps via the transcription factor XBP1
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XBP1
Proinflammatory cytokine
ATF6
ATF4
Activating transcription factor
Tauroursodeoxycholic acid
In the endoplasmic reticulum (ER), secretory and membrane proteins are properly folded and modified, and the failure of these processes leads to ER stress. At the same time, unfolded protein response (UPR) genes are activated to maintain homeostasis. Despite the thorough characterization of the individual gene regulation of UPR genes to date, further investigation of the mutual regulation among UPR genes is required to understand the complex mechanism underlying the ER stress response. In this study, we aimed to reveal a gene regulatory network formed by UPR genes, including immunoglobulin heavy chain-binding protein (BiP), X-box binding protein 1 (XBP1), C/EBP [CCAAT/enhancer-binding protein]-homologous protein (CHOP), PKR-like endoplasmic reticulum kinase (PERK), inositol-requiring 1 (IRE1), activating transcription factor 6 (ATF6), and ATF4. For this purpose, we focused on promoter-luciferase reporters for BiP, XBP1, and CHOP genes, which bear an ER stress response element (ERSE), and p5 × ATF6-GL3, which bears an unfolded protein response element (UPRE). We demonstrated that the luciferase activities of the BiP and CHOP promoters were upregulated by all the UPR genes, whereas those of the XBP1 promoter and p5 × ATF6-GL3 were upregulated by all the UPR genes except for BiP, CHOP, and ATF4 in HeLa cells. Therefore, an ERSE- and UPRE-centered gene regulatory network of UPR genes could be responsible for the robustness of the ER stress response. Finally, we revealed that BiP protein was degraded when cells were treated with DNA-damaging reagents, such as etoposide and doxorubicin; this finding suggests that the expression level of BiP is tightly regulated at the post-translational level, rather than at the transcriptional level, in the presence of DNA damage.
ATF6
XBP1
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Activating transcription factor
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Purpose To investigate the activation of three unfolded protein response (UPR) pathways in the lenses of age-related, high myopia-related and congenital cataracts. Methods and Materials Lens specimens were collected from patients during small incision cataract surgery. Lenses from young cadaver eyes were collected as normal controls. Real-time PCR and Western blotting were performed to detect the expression of GRP78, p-eIF2α, spliced XBP1, ATF6, ATF4 and p-IRE1α in the lenses of normal human subjects and patients with age-related, myopia-related or congenital cataracts. Results In the lenses of the age-related and high myopia-related cataract groups, the protein levels of ATF6, p-eIF2α and p-IRE1α and the gene expression levels of spliced XBP1, GRP78, ATF6 and ATF4 were greatly increased. Additionally, in the congenital cataract group, the protein levels of p-eIF2α and p-IRE1α and the gene expression levels of spliced XBP1, GRP78 and ATF4 were greatly increased. However, the protein and gene expression levels of ATF6 were not up-regulated in the congenital cataract group compared with the normal control group. Conclusions The UPR is activated via different pathways in the lenses of age-related, high myopia-related and congenital cataracts. UPR activation via distinct pathways might play important roles in cataractogenesis mechanisms in different types of cataracts.
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Abstract Mammalian inositol-requiring enzyme 1α (IRE1α) is the most conserved of all endoplasmic reticulum (ER) stress sensors, which includes activating transcription factor (ATF) 6 and double-stranded RNA-dependent protein kinase (PKR)-like ER kinase (PERK). IRE1α has been known to splice X-box binding protein 1 (XBP1) mRNA, which is induced by ATF6 under ER stress. This spliced XBP1 mRNA is translated into the active transcription factor that promotes the expression of specific genes to alleviate ER stress. Herein, we report that in addition to the induction of XBP1 expression by ATF6, IRE1α expression is induced by ATF4, which is downstream of PERK, under ER stress. Increased IRE1α expression results in a higher splicing ratio of XBP1 mRNA. This effect was not transient and affected not only the intensity but also the duration of the activated state of this pathway. These multiple regulatory mechanisms may modulate the response to various levels or types of ER stress.
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EIF-2 kinase
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Methylglyoxal (MGO) is considered responsible for the detrimental effects of high blood glucose. MGO is produced as a by-product of the glycolysis pathway. While the glyoxalase system removes it, the system fails in people with diabetes. MGO concentration is detected as elevated in these patients. Endoplasmic reticulum (ER) stress may play a role in atherosclerosis progression and vascular diseases. If ER stress persists, it may result in apoptosis of the cell. As a result, stabilized plaque structure by these cells may be ruptured and cause a stroke. This study aimed to investigate whether MGO can induce ER stress and apoptosis in vascular smooth muscle cells (VSMCs). Also, the effects of aminoguanidine hydrochloride (AGH), 4-phenylbutyric acid (4-PBA), and tauroursodeoxycholic acid (TUDCA) were scrutinized to relieve ER stress. VSMCs were isolated from rat aorta and cultured primary. PERK phosphorylation, IRE1α, ATF6, BiP (Grp78), and CHOP expressions were detected by the western blot technique. A caspase-3 assay kit measured the apoptosis. MGO could stimulate the main three ER stress pathways, PERK phosphorylation, IRE1α, and ATF6 expressions in a time- and concentration-dependent manner. Furthermore, AGH, 4-PBA, and TUDCA alleviated MGO-induced ER stress. However, we detected neither an increase in CHOP expression nor apoptosis in VSMCs. This study shows that MGO induces ER stress even at low concentrations in VSMCs. The impaired glyoxalase system may cause MGO accumulation and result in persisted ER stress. Supposing that ER stress is not mitigated, this table might be finalized in cell apoptosis, plaque rupture, and stroke.
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XBP1
ATF6
Protein kinase R
EIF-2 kinase
ATF4
eIF2
Integrated stress response
Coronavirus
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Endoplasmic reticulum stress (ERS) in the retinal Müller cells is a key factor contributing to the retinal inflammation and vascular leakage in diabetic retinopathy (DR). This study was to investigate the underlying mechanisms through which the 3 main unfolded protein response (UPR) pathways regulate ERS and to examine the expression levels of vascular endothelial growth factor (VEGF) in Müller cells in vitro.Rat Müller cell lines were stimulated with high glucose to mimic a diabetic environment in vitro. PKR-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and activating transcription factor 6 (ATF6) were downregulated or upregulated with shRNA or overexpression plasmids. The transfected Müller cells were cultivated in high glucose medium for 48 hours. Expression of glucose-regulated protein 78 (GRP78), activating transcription factor 4 (ATF4), X-box binding protein 1 (XBP1), ATF6, and VEGF was examined with immunofluorescence and western blot.Our data indicated that ERS was found in both high glucose and osmotic control groups. Overexpression or downregulation of UPR pathways effectively increased or reduced the production of GRP78, ATF4, XBP1, ATF6, and VEGF, respectively. These 3 signaling pathways had similar regulatory effects on VEGF.The 3 UPR-mediated inflammatory pathways were dependent on each other. Inhibition any of these signaling pathways in UPR might be a potential therapeutic target for DR.
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Accumulating evidence suggests that fetal growth restriction (FGR) leads to the development of diabetes mellitus in adults. The aim of this study was to investigate the effect of protein malnutrition in utero on the pancreatic unfolded protein response (UPR) pathway in FGR offspring. An FGR model was developed by feeding a low-protein diet to pregnant rats throughout gestation. Eighty-four UPR pathway components in the pancreas were investigated by quantitative PCR arrays and confirmed by qPCR and western blotting. Activating transcription factor (Atf4 and Atf6), herpud1, protein kinase R-like endoplasmic reticulum kinase (Perk), X-box binding protein 1 (Xbp1), and the phosphorylation of eIF2α were upregulated, while cyclic AMP-responsive element-binding protein 3-like protein was markedly downregulated in FGR fetuses compared with controls. Investigation in adult offspring revealed temporal changes, for most UPR factors restored to normal, except that dysregulation of Atf6 and Creb3l3 maintained until adulthood. Moreover, autophagy was suppressed in FGR fetal pancreas and may be associated with decreased activation of AMP-activated protein kinase (Ampk). Apoptosis regulators Bax and cleaved-caspase 3 and 9 were upregulated in FGR fetal pancreas. Given that islet size and number were decreased in FGR fetus, we speculated that the aberrant intrauterine milieu impaired UPR signaling in fetal pancreas development. Whether these alterations early in life contribute to the predisposition of FGR fetuses to adult metabolic disorders invites further exploration.
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To investigate the anti-apoptotic mechanism of leptin in non-small cell lung cancer.The influences of leptin on apoptosis were investigated, analyzing the mechanism that triggers growth of A549 cells. The effects of leptin on cell proliferation were examined by XTT analysis. Leptin, C/EBP homologous protein (CHOP), phosphorylated-PKR-like ER kinase (p-Perk), inositol requiring proteins-1, spliced X-box transcription factor-1 (XBP1), cleaved activating transcription factor-6 (ATF6), eukaryotic translation initiation factor-2α, caspase-12 and CHOP protein were detected in four groups by western blot, and endoplasmic reticulum (ER) stress related mRNA were detected by reverse transcription PCR.The expression of leptin in A549 and leptin transfected cells inhibited cisplatin activated ER stress-associated mRNA transcription and protein activation. Two ER stress unfolded protein response pathways, PERK and ATF6, were involved, and XBP1 and tumor necrosis factor receptor-associated factor 2 (TRAF2) were increased significantly when treated with cisplatin in A549-siRNA against leptin cells. Furthermore, CHOP expression was inhibited upon leptin expression in A549, LPT-PeP and LPT-EX cells.Leptin serves as an important factor that promotes the growth of A549 cells through blocking ER stress-mediated pathways. This blocking is triggered by p-Perk and ATF6 via inhibition of CHOP expression.
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The glycine transporter GLYT1 and the cystine-glutamate exchanger xCT have been identified as targets of the eIF2α stress response pathway and the transcription factor ATF4. To determine the role of these transporters in the intestinal response to stress we have examined regulation of expression of GLYT1 and xCT in the human colon carcinoma cell line Caco-2 during ER-stress and knockdown of the key transcription factors, ATF4, X-box-binding protein 1 (XBP1) and ATF6, involved in the unfolded protein response. Cells exposed to tunicamycin, a stimulator of ER-stress, showed greatly (8–10 fold) increased expression of GLYT1 and xCT mRNAs, measured by quantitative PCR, but little change in expression of the peptide transporter PepT1 mRNA. Expression of markers of ER-stress, DNA-damage inducible transcript 3 (DDIT3, also known as CHOP) and glucose-regulated protein-78 (GRP-78) was also greatly increased. siRNA knockdown of ATF4 resulted in decreased expression of GLYT1 and xCT mRNAs but had no effect on PepT1. Knockdown of XBP1 or ATF6 did not alter expression of any gene. These data suggest that GLYT1 and xCT are specific targets of ATF4 in intestinal cells. We suggest that increased expression of these transporters induced by stress leads to increased uptake of glycine and cystine, required for glutathione synthesis, and thus to increased intracellular antioxidant capacity.
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Integrated stress response
Activating transcription factor
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