Andrographolide Mitigates Unfolded Protein Response Pathway andApoptosis Involved in Chikungunya virus Infection

2020 ◽  
Vol 23 ◽  
Author(s):  
Swati Gupta ◽  
KP Mishra ◽  
Bhuvnesh Kumar ◽  
SB Singh ◽  
Lilly Ganju
Keyword(s):  
Protein Expression ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Chikungunya Virus ◽  
Rna Virus ◽  
Apoptosis Pathway ◽  
Unfolded Protein ◽  
Induced Apoptosis ◽  
Protein Response ◽  
Upr Pathway

Background: Chikungunya virus (CHIKV) is an arthropod-borne RNA virus which induces host endoplasmic reticulum (ER) stress by accumulating unfolded or misfolded proteins. ER stress activates the unfolded protein response (UPR) pathway to enable proper protein folding and maintain cellular homeostasis. There is no approved drug or vaccine available for CHIKV treatment, therefore, a pharmacological countermeasure is warranted for preventing CHIKV infection. Objective: With a view to find a treatment modality for chikungunya infection, “andrographolide”; a plant-derived diterpenoid with reported antiviral, anti-inflammatory and immunomodulatory effects, was used to investigate its role in chikungunya induced unfolded protein stress and apoptosis. Methods: Cells and supernatant collected on andrographolide and VER-155008; a GRP78 inhibitor, treatment in CHIKV infected and mock-infected THP-1 cells were tested for differential expression of UPR pathway proteins including GRP78, PERK, EIF-2α, IRE-1α, XBP-1 and ATF6. Further, the inflammasome and apoptosis pathway proteins i.e. caspase-1, caspase-3 and PARP were tested by immunoblotting and cytokines i.e. IL-1β, IL-6 and IFN-γ were tested by ELISA. Results: Andrographolide treatment in CHIKV infected THP-1 cells significantly reduced IRE1α and downstream spliced XBP1 protein expression. Further, CHIKV induced apoptosis and viral protein expression was also reduced on andrographolide treatment. A comparative analysis of andrographolide verses VER-155008, confirmed that andrographolide surpasses the effects of VER-155008 in suppressing the CHIKV induced ER stress. Conclusion: The study, therefore, confirms that andrographolide is a potential remedy for chikungunya infection and suppresses CHIKV induced ER stress and apoptosis.

scholarly journals The unfolded protein response controls ER stress-induced apoptosis of lung epithelial cells through angiotensin generation

2016 ◽  
Vol 311 (5) ◽  
pp. L846-L854 ◽  
Author(s):  
Hang Nguyen ◽  
Bruce D. Uhal
Keyword(s):  
Epithelial Cells ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Cathepsin D ◽  
Lung Epithelial Cells ◽  
Chemical Chaperone ◽  
Unfolded Protein ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Protein Response

Recent work from this laboratory showed that endoplasmic reticulum (ER) stress-induced apoptosis of alveolar epithelial cells (AECs) is regulated by the autocrine angiotensin (ANG)II/ANG1-7 system. The proteasome inhibitor MG132 or surfactant protein C (SP-C) BRICHOS domain mutation G100S induced apoptosis in human AECs by activating the proapoptotic cathepsin D and reducing antiapoptotic angiotensin converting enzyme-2 (ACE-2). This study tested the hypothesis that ER stress-induced apoptosis of human AECs might be mediated by influence of the unfolded protein response (UPR) on the autocrine ANGII/ANG1-7 system. A549 cells were challenged with MG132 or SP-C BRICHOS domain mutant G100S to induce ER stress and activation of UPR pathways. The results showed that either MG132 or G100S SP-C mutation activated all three canonical pathways of the UPR (IRE1/XBP1, ATF6, and PERK/eIF2α), which led to a significant increase in cathepsin D or in TACE (an ACE-2 ectodomain shedding enzyme) and eventually caused AEC apoptosis. However, ER stress-induced AEC apoptosis could be prevented by chemical chaperone or by UPR blockers. It is also suggested that ATF6 and IRE1 pathways might play important role in regulation of angiotensin system. These data demonstrate that ER stress induces apoptosis in human AECs through mediation of UPR pathways, which in turn regulate the autocrine ANGII/ANG1-7 system. They also demonstrated that ER stress-induced AEC apoptosis can be blocked by inhibition of UPR signaling pathways.

Abstract 210: Flavin Containing Monooxygenase 2 Confers Cardiac Protection via Unfolded Protein Response Signaling Modulated by Disulfide Bond Catalysis

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_4) ◽  
Author(s):  
Qingnian Liu ◽  
Yue Tao ◽  
Hao Ding ◽  
Changchen Xiao ◽  
Yu Zhou ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Disulfide Bond ◽  
Active Site ◽  
Cardiac Protection ◽  
Unfolded Protein ◽  
Protein Response ◽  
Upr Pathway

Introduction: Myocardial infarction (MI) is characterized by cardiac dysfunction and increased cardiomyocyte death, induced mainly by apoptosis. Using an unbiased transcriptome analysis, we identified flavin containing monooxygenase 2 (FMO2) as one of the top-ranked genes involved in the process of MI. In this study, we investigate the roles of FMO2 in ischemic injury and its potential mechanisms. Hypothesis: FMO2 exhibits the cardiac protection from MI injury. Methods: Male SD rats receiving either adeno-associated virus serotype 9 containing FMO2 shRNA particles (AAV-shFMO2) or FMO2 (AAV-FMO2), and FMO2 knockout rats were subjected to myocardial infarction surgery. Cardiac function, fibrosis, and apoptosis were examined in these rats and related cellular and molecular mechanisms were investigated. Results: Cardiac ischemia injury was associated with significant increases of FMO2 levels both in ex vivo and in vivo models. Loss of FMO2 significantly enhanced cardiomyocyte apoptosis and deteriorated cardiac function accompanied by augmented infarct size in infarcted rat hearts, while elevated expression of FMO2 exhibited the opposite results. Mechanically, located on the ER membrane, FMO2 inhibited activation of ER stress-initiated apoptotic proteins including caspase 12 and C/EBP homologous protein (CHOP), via down-regulating upstream unfolded protein response (UPR) pathway. Furthermore, we found that FMO2, as a novel chaperone in ER, directly catalyzed disulfide-bond synthesis to facilitate proteins folding. Finally, structure analysis of FMO2 revealed the active site GVSG for disulfide-bond catalysis, which was confirmed by the molecular docking experiment of GSH with FMO2. However, FMO2 with GVSG mutation failed to catalyze disulfide-bond formation and lost protection from ER stress or apoptosis in cardiomyocytes. Conclusion: FMO2 confers cardiac protection from ischemic damage due to improved cardiomyocyte apoptosis through UPR pathway, which is mediated by disulfide-bond catalysis at GVSG active site. Our findings uncover a novel FMO2-involved regulatory mechanism which could serves as a potential therapeutic target for ischemic cardiovascular diseases.

scholarly journals Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4907-4916 ◽  
Author(s):  
Esther A. Obeng ◽  
Louise M. Carlson ◽  
Delia M. Gutman ◽  
William J. Harrington ◽  
Kelvin P. Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Proteasome Inhibitors ◽  
26S Proteasome ◽  
Secretory Cells ◽  
B Cell Differentiation ◽  
Unfolded Protein ◽  
Induced Apoptosis ◽  
Protein Response

AbstractMultiple myeloma (MM) is an incurable plasma cell malignancy. The 26S proteasome inhibitor, bortezomib, selectively induces apoptosis in MM cells; however, the nature of its selectivity remains unknown. Here we demonstrate that 5 different MM cell lines display similar patterns of sensitivity to 3 proteasome inhibitors (PIs) but respond differently to specific NF-κB inhibition. We further show that PIs initiate the unfolded protein response (UPR), a signaling pathway activated by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). Consistent with reports that prosurvival/physiologic UPR components are required for B-cell differentiation into antibody-secreting cells, we found that MM cells inherently expressed the ER chaperones GRP78/Bip and GRP94/gp96. However, bortezomib rapidly induced components of the proapoptotic/terminal UPR, including PERK, the ER stress–specific eIF-2α kinase; ATF4, an ER stress–induced transcription factor; and its proapoptotic target, CHOP/GADD153. Consistent with our hypothesis that PIs induce the accumulation of misfolded ER-processed proteins, we found that the amount of immunoglobulin subunits retained within MM cells correlated with their sensitivity to PIs. These findings suggest that MM cells have a lower threshold for PI-induced UPR induction and ER stress–induced apoptosis because they constitutively express ER stress survival factors to function as secretory cells.

Expression of the hyperphosphorylated tau attenuates ER stress-induced apoptosis with upregulation of unfolded protein response

APOPTOSIS ◽  
2012 ◽  
Vol 17 (10) ◽  
pp. 1039-1049 ◽  
Author(s):  
Xin-An Liu ◽  
Jie Song ◽  
Qian Jiang ◽  
Qun Wang ◽  
Qing Tian ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Hyperphosphorylated Tau ◽  
Unfolded Protein ◽  
Induced Apoptosis ◽  
Protein Response

scholarly journals Reduced endoplasmic reticulum stress-induced apoptosis and impaired unfolded protein response in TRPC3-deficient M1 macrophages

2014 ◽  
Vol 307 (6) ◽  
pp. C521-C531 ◽  
Author(s):  
Sumeet Solanki ◽  
Prabhatchandra R. Dube ◽  
Jean-Yves Tano ◽  
Lutz Birnbaumer ◽  
Guillermo Vazquez
Keyword(s):  
Bone Marrow ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Unfolded Protein ◽  
Macrophage Apoptosis ◽  
Induced Apoptosis ◽  
Protein Response

Endoplasmic reticulum (ER) stress is a prominent mechanism of macrophage apoptosis in advanced atherosclerotic lesions. Recent studies from our laboratory showed that advanced atherosclerotic plaques in Apoe−/− mice with bone marrow deficiency of the calcium-permeable channel Transient Receptor Potential Canonical 3 (TRPC3) are characterized by reduced areas of necrosis and fewer apoptotic macrophages than animals transplanted with Trpc3+/+ bone marrow. In vitro, proinflammatory M1 but not anti-inflammatory M2 macrophages derived from Trpc3−/−Apoe−/− animals exhibited reduced ER stress-induced apoptosis. However, whether this was due to a specific effect of TRPC3 deficiency on macrophage ER stress signaling remained to be determined. In the present work we used polarized macrophages derived from mice with macrophage-specific deficiency of TRPC3 to examine the expression level of ER stress markers and the activation status of some typical mediators of macrophage apoptosis. We found that the reduced susceptibility of TRPC3-deficient M1 macrophages to ER stress-induced apoptosis correlates with an impaired unfolded protein response (UPR), reduced mitochondrion-dependent apoptosis, and reduced activation of the proapoptotic molecules calmodulin-dependent protein kinase II and signal transducer and activator of transcription 1. Notably, none of these pathways was altered in TRPC3-deficient M2 macrophages. These findings show for the first time an obligatory requirement for a member of the TRPC family of cation channels in ER stress-induced apoptosis in macrophages, underscoring a rather selective role of the TRPC3 channel on mechanisms related to the UPR signaling in M1 macrophages.

scholarly journals WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome

2021 ◽  
pp. jmedgenet-2020-107257
Author(s):  
Kun Hu ◽  
Malgorzata Zatyka ◽  
Dewi Astuti ◽  
Nicola Beer ◽  
Renuka P Dias ◽  
...  
Keyword(s):  
Protein Expression ◽  
Er Stress ◽  
Optic Atrophy ◽  
Wolfram Syndrome ◽  
Luciferase Reporter ◽  
Compound Heterozygous ◽  
Nonsense Mutations ◽  
Functional Studies ◽  
Unfolded Protein ◽  
Protein Response

BackgroundWolfram syndrome (WFS) is a rare disorder characterised by childhood-onset diabetes mellitus and progressive optic atrophy. Most patients have variants in the WFS1 gene. We undertook functional studies of WFS1 variants and correlated these with WFS1 protein expression and phenotype.Methods9 patients with a clinical diagnosis of WFS were studied with quantitative PCR for markers of endoplasmic reticulum (ER) stress and immunoblotting of fibroblast protein extracts for WFS1 protein expression. Luciferase reporter assay was used to assess ATF-6 dependent unfolded protein response (UPR) activation.Results6 patients with compound heterozygous nonsense mutations in WFS1 had no detectable WFS1 protein expression; 3 patients with missense variants had 4%, 45% and 48% WFS1 protein expression. One of these also had an OPA1 mutation and was reclassified as autosomal dominant optic atrophy-plus syndrome. There were no correlations between ER stress marker mRNA and WFS1 protein expression. ERSE-luciferase reporter indicated activation of the ATF6 branch of UPR in two patients tested. Patients with partial WFS1 expression showed milder visual acuity impairment (asymptomatic or colour blind only), compared with those with absent expression (registered severe vision impaired) (p=0.04). These differences remained after adjusting for duration of optic atrophy.ConclusionsPatients with WFS who have partial WFS1 protein expression present with milder visual impairment. This suggests a protective effect of partial WFS1 protein expression on the severity and perhaps progression of vision impairment and that therapies to increase residual WFS1 protein expression may be beneficial.

scholarly journals Effectors Targeting the Unfolded Protein Response during Intracellular Bacterial Infection

2021 ◽  
Vol 9 (4) ◽  
pp. 705
Author(s):  
Manal H. Alshareef ◽  
Elizabeth L. Hartland ◽  
Kathleen McCaffrey
Keyword(s):  
Bacterial Infection ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Host Defense ◽  
Effector Proteins ◽  
Dual Nature ◽  
Unfolded Protein ◽  
Bacterial Replication ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) is a homeostatic response to endoplasmic reticulum (ER) stress within eukaryotic cells. The UPR initiates transcriptional and post-transcriptional programs to resolve ER stress; or, if ER stress is severe or prolonged, initiates apoptosis. ER stress is a common feature of bacterial infection although the role of the UPR in host defense is only beginning to be understood. While the UPR is important for host defense against pore-forming toxins produced by some bacteria, other bacterial effector proteins hijack the UPR through the activity of translocated effector proteins that facilitate intracellular survival and proliferation. UPR-mediated apoptosis can limit bacterial replication but also often contributes to tissue damage and disease. Here, we discuss the dual nature of the UPR during infection and the implications of UPR activation or inhibition for inflammation and immunity as illustrated by different bacterial pathogens.

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