scholarly journals West Nile Virus Infection Activates the Unfolded Protein Response, Leading to CHOP Induction and Apoptosis

2007 ◽  
Vol 81 (20) ◽  
pp. 10849-10860 ◽  
Author(s):  
Guruprasad R. Medigeshi ◽  
Alissa M. Lancaster ◽  
Alec J. Hirsch ◽  
Thomas Briese ◽  
W. Ian Lipkin ◽  
...  
Keyword(s):  
Transcription Factor ◽  
West Nile Virus ◽  
Unfolded Protein Response ◽  
Neuronal Damage ◽  
Initiation Factor ◽  
West Nile ◽  
Human Neuroblastoma ◽  
Unfolded Protein ◽  
Infected Cells ◽  
Protein Response

ABSTRACT West Nile virus (WNV)-mediated neuronal death is a hallmark of WNV meningitis and encephalitis. However, the mechanisms of WNV-induced neuronal damage are not well understood. We investigated WNV neuropathogenesis by using human neuroblastoma cells and primary rat hippocampal neurons. We observed that WNV activates multiple unfolded protein response (UPR) pathways, leading to transcriptional and translational induction of UPR target genes. We evaluated the role of the three major UPR pathways, namely, inositol-requiring enzyme 1-dependent splicing of X box binding protein 1 (XBP1) mRNA, activation of activating transcription factor 6 (ATF6), and protein kinase R-like endoplasmic reticulum (ER) kinase-dependent eukaryotic initiation factor 2α (eIF2α) phosphorylation, in WNV-infected cells. We show that XBP1 is nonessential or can be replaced by other UPR pathways in WNV replication. ATF6 was rapidly degraded by proteasomes, consistent with induction of ER stress by WNV. We further observed a transient phosphorylation of eIF2α and induction of the proapoptotic cyclic AMP response element-binding transcription factor homologous protein (CHOP). WNV-infected cells exhibited a number of apoptotic phenotypes, such as (i) induction of growth arrest and DNA damage-inducible gene 34, (ii) activation of caspase-3, and (iii) cleavage of poly(ADP-ribose) polymerase. The expression of WNV nonstructural proteins alone was sufficient to induce CHOP expression. Importantly, WNV grew to significantly higher viral titers in chop − / − mouse embryonic fibroblasts (MEFs) than in wild-type MEFs, suggesting that CHOP-dependent premature cell death represents a host defense mechanism to limit viral replication that might also be responsible for the widespread neuronal loss observed in WNV-infected neuronal tissue.

scholarly journals Activating Transcription Factor 4 Is Translationally Regulated by Hypoxic Stress

2004 ◽  
Vol 24 (17) ◽  
pp. 7469-7482 ◽  
Author(s):  
Jaime D. Blais ◽  
Vasilisa Filipenko ◽  
Meixia Bi ◽  
Heather P. Harding ◽  
David Ron ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Microarray Analysis ◽  
Initiation Factor ◽  
Hypoxic Stress ◽  
Unfolded Protein ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Transcription Factor 4

ABSTRACT Hypoxic stress results in a rapid and sustained inhibition of protein synthesis that is at least partially mediated by eukaryotic initiation factor 2α (eIF2α) phosphorylation by the endoplasmic reticulum (ER) kinase PERK. Here we show through microarray analysis of polysome-bound RNA in aerobic and hypoxic HeLa cells that a subset of transcripts are preferentially translated during hypoxia, including activating transcription factor 4 (ATF4), an important mediator of the unfolded protein response. Changes in mRNA translation during the unfolded protein response are mediated by PERK phosphorylation of the translation initiation factor eIF2α at Ser-51. Similarly, PERK is activated and is responsible for translational regulation under hypoxic conditions, while inducing the translation of ATF4. The overexpression of a C-terminal fragment of GADD34 that constitutively dephosphorylates eIF2α was able to attenuate the phosphorylation of eIF2α and severely inhibit the induction of ATF4 in response to hypoxic stress. These studies demonstrate the essential role of ATF4 in the response to hypoxic stress, define the pathway for its induction, and reveal that GADD34, a target of ATF4 activation, negatively regulates the eIF2α-mediated inhibition of translation. Taken with the concomitant induction of additional ER-resident proteins identified by our microarray analysis, this study suggests an important integrated response between ER signaling and the cellular adaptation to hypoxic stress.

scholarly journals Inhibition of IRE1α-mediated XBP1 mRNA cleavage by XBP1 reveals a novel regulatory process during the unfolded protein response

2017 ◽  
Vol 2 ◽  
pp. 36 ◽  
Author(s):  
Fiona Chalmers ◽  
Bernadette Sweeney ◽  
Katharine Cain ◽  
Neil J. Bulleid
Keyword(s):  
Transcription Factor ◽  
Unfolded Protein Response ◽  
Target Genes ◽  
Feedback Mechanism ◽  
Ribonuclease Activity ◽  
Stable Cell Line ◽  
Factor X ◽  
Unfolded Protein ◽  
Xbp1 Mrna ◽  
Protein Response

Background: The mammalian endoplasmic reticulum (ER) continuously adapts to the cellular secretory load by the activation of an unfolded protein response (UPR).  This stress response results in expansion of the ER, upregulation of proteins involved in protein folding and degradation, and attenuation of protein synthesis.  The response is orchestrated by three signalling pathways each activated by a specific signal transducer, either inositol requiring enzyme α (IRE1α), double-stranded RNA-activated protein kinase-like ER kinase (PERK) or activating transcription factor 6 (ATF6).  Activation of IRE1α results in its oligomerisation, autophosphorylation and stimulation of its ribonuclease activity.  The ribonuclease initiates the splicing of an intron from mRNA encoding the transcription factor, X-box binding protein 1 (XBP1), as well as degradation of specific mRNAs and microRNAs. Methods: To investigate the consequence of expression of exogenous XBP1, we generated a stable cell-line expressing spliced XBP1 mRNA under the control of an inducible promotor.  Results: Following induction of expression, high levels of XBP1 protein were detected, which allowed upregulation of target genes in the absence of induction of the UPR.  Remarkably under stress conditions, the expression of exogenous XBP1 repressed splicing of endogenous XBP1 mRNA without repressing the activation of PERK.  Conclusions: These results illustrate that a feedback mechanism exists to attenuate activation of the Ire1α ribonuclease activity in the presence of XBP1.

scholarly journals Palmitate deranges erythropoietin production via transcription factor ATF4 activation of unfolded protein response

2018 ◽  
Vol 94 (3) ◽  
pp. 536-550 ◽  
Author(s):  
Thitinun Anusornvongchai ◽  
Masaomi Nangaku ◽  
Tzu-Ming Jao ◽  
Chia-Hsien Wu ◽  
Yu Ishimoto ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Erythropoietin Production ◽  
Protein Response

Abstract 3760: Atherogenic Affects Of Arsenic: Role Of Endoplasmic Reticulum Stress And Unfolded Protein Response

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Petra Haberzettl ◽  
Elena Vladykovskaya ◽  
Oleg Barski ◽  
Srinivas Sithu ◽  
Stanley D’Souza ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Unfolded Protein Response ◽  
Atherosclerotic Lesion ◽  
The United States ◽  
Hazardous Substance ◽  
Dependent Manner ◽  
Lesion Formation ◽  
Chemical Chaperone ◽  
Unfolded Protein ◽  
Protein Response

Arsenic is a global water contaminant and EPA has listed arsenic as a high priority hazardous substance in the United States. Epidemiological studies suggest that chronic arsenic ingestion increases cardiovascular disease in humans, particularly, carotid atherosclerosis. However, mechanisms of arsenic-induced atherogenesis are unknown. We examined the effect of arsenic exposure on early lesion formation in apoE-null mice maintained on water supplemented with (0, 1, 5 and 50 ppm; 3–16 weeks of age) sodium arsenite. Arsenic, did not affect plasma cholesterol but decreased the triglycerides by 18±4 % (P<0.05). NMR analysis of the lipoproteins showed a significant decrease in the abundance of large VLDL particle (>60 nm diameter). Despite a significant decrease in plasma triglyceride, atherosclerotic lesion formation was significantly increased (2– 4 fold; P<0.05 for all doses) in the aortic sinus and the aortic arch of the arsenic-fed mice in a dose dependent manner. Immunohistochemical analysis showed significant increase in the accumulation of macrophages, expression of MCP-1 and unfolded protein response (UPR) dependent activating transcription factor (ATF)-4 and ATF3, in the lesions of arsenic (1ppm) exposed mice. In vitro , arsenic (5–25 μM), significantly increased the expression of ICAM-1, transmigration of differentiated monocytes and expression of the pro-inflammatory cytokine IL-8 in vascular endothelial cells (vEC). Arsenic, also increased the expression of ER-chaperones Grp 78, HERP and calnexin (2– 6 fold; P<0.01). Examination of the effect of arsenic on UPR showed that arsenic, induced the splicing of IRE-1 dependent, bZIP transcription factor XBP-1(alarm phase) and increased the phosphorylation of eIF2α (PERK mediated adaptive phase) by 3 fold (P<0.01) in vEC. Arsenic also induced the expression of the downstream effecter proteins of eIF2α-ATF3 (8 fold; P<0.01) and pro-apoptotic protein CHOP (4 fold; P<0.01) in vEC. Chemical chaperone, phenyl butyric acid (PBA), attenuated the arsenic-induced expression of ATF3 (>90%; P<0.001) and CHOP (>90%; P<0.001). These data suggest that ER-stress and UPR could exacerbate arsenic-induced vascular inflammation and promote atherogenesis.

scholarly journals Ceapins are a new class of unfolded protein response inhibitors, selectively targeting the ATF6α branch

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Ciara M Gallagher ◽  
Carolina Garri ◽  
Erica L Cain ◽  
Kenny Kean-Hooi Ang ◽  
Christopher G Wilson ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Proteolytic Processing ◽  
Unfolded Protein ◽  
New Class ◽  
Cancer Models ◽  
Membrane Bound ◽  
The Unfolded Protein Response ◽  
Protein Response

The membrane-bound transcription factor ATF6α plays a cytoprotective role in the unfolded protein response (UPR), required for cells to survive ER stress. Activation of ATF6α promotes cell survival in cancer models. We used cell-based screens to discover and develop Ceapins, a class of pyrazole amides, that block ATF6α signaling in response to ER stress. Ceapins sensitize cells to ER stress without impacting viability of unstressed cells. Ceapins are highly specific inhibitors of ATF6α signaling, not affecting signaling through the other branches of the UPR, or proteolytic processing of its close homolog ATF6β or SREBP (a cholesterol-regulated transcription factor), both activated by the same proteases. Ceapins are first-in-class inhibitors that can be used to explore both the mechanism of activation of ATF6α and its role in pathological settings. The discovery of Ceapins now enables pharmacological modulation all three UPR branches either singly or in combination.

scholarly journals Inhibition of IRE1α-mediated XBP1 mRNA cleavage by XBP1 reveals a novel regulatory process during the unfolded protein response

2017 ◽  
Vol 2 ◽  
pp. 36 ◽  
Author(s):  
Fiona Chalmers ◽  
Marcel van Lith ◽  
Bernadette Sweeney ◽  
Katharine Cain ◽  
Neil J. Bulleid
Keyword(s):  
Transcription Factor ◽  
Unfolded Protein Response ◽  
Target Genes ◽  
Feedback Mechanism ◽  
Ribonuclease Activity ◽  
Stable Cell Line ◽  
Factor X ◽  
Unfolded Protein ◽  
Xbp1 Mrna ◽  
Protein Response

Background: The mammalian endoplasmic reticulum (ER) continuously adapts to the cellular secretory load by the activation of an unfolded protein response (UPR).  This stress response results in expansion of the ER, upregulation of proteins involved in protein folding and degradation, and attenuation of protein synthesis.  The response is orchestrated by three signalling pathways each activated by a specific signal transducer, either inositol requiring enzyme α (IRE1α), double-stranded RNA-activated protein kinase-like ER kinase (PERK) or activating transcription factor 6 (ATF6).  Activation of IRE1α results in its oligomerisation, autophosphorylation and stimulation of its ribonuclease activity.  The ribonuclease initiates the splicing of an intron from mRNA encoding the transcription factor, X-box binding protein 1 (XBP1), as well as degradation of specific mRNAs and microRNAs. Methods: To investigate the consequence of expression of exogenous XBP1, we generated a stable cell-line expressing spliced XBP1 mRNA under the control of an inducible promotor. Results: Following induction of expression, high levels of XBP1 protein were detected, which allowed upregulation of target genes in the absence of induction of the UPR.  Remarkably under stress conditions, the expression of exogenous XBP1 repressed splicing of endogenous XBP1 mRNA without repressing the activation of PERK. Conclusions: These results illustrate that a feedback mechanism exists to attenuate Ire1α ribonuclease activity in the presence of XBP1.

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