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 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.

scholarly journals Unfolded protein response transducer IRE1-mediated signaling independent of XBP1 mRNA splicing is not required for growth and development of medaka fish

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Tokiro Ishikawa ◽  
Makoto Kashima ◽  
Atsushi J Nagano ◽  
Tomoko Ishikawa-Fujiwara ◽  
Yasuhiro Kamei ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Unfolded Protein Response ◽  
Growth And Development ◽  
Constitutive Expression ◽  
Medaka Fish ◽  
Jnk Pathway ◽  
Unfolded Protein ◽  
Xbp1 Mrna ◽  
Protein Response

When activated by the accumulation of unfolded proteins in the endoplasmic reticulum, metazoan IRE1, the most evolutionarily conserved unfolded protein response (UPR) transducer, initiates unconventional splicing of XBP1 mRNA. Unspliced and spliced mRNA are translated to produce pXBP1(U) and pXBP1(S), respectively. pXBP1(S) functions as a potent transcription factor, whereas pXBP1(U) targets pXBP1(S) to degradation. In addition, activated IRE1 transmits two signaling outputs independent of XBP1, namely activation of the JNK pathway, which is initiated by binding of the adaptor TRAF2 to phosphorylated IRE1, and regulated IRE1-dependent decay (RIDD) of various mRNAs in a relatively nonspecific manner. Here, we conducted comprehensive and systematic genetic analyses of the IRE1-XBP1 branch of the UPR using medaka fish and found that the defects observed in XBP1-knockout or IRE1-knockout medaka were fully rescued by constitutive expression of pXBP1(S). Thus, the JNK and RIDD pathways are not required for the normal growth and development of medaka. The unfolded protein response sensor/transducer IRE1-mediated splicing of XBP1 mRNA encoding its active downstream transcription factor to maintain the homeostasis of the endoplasmic reticulum is sufficient for growth and development of medaka fish.

scholarly journals XBP-1 Regulates a Subset of Endoplasmic Reticulum Resident Chaperone Genes in the Unfolded Protein Response

2003 ◽  
Vol 23 (21) ◽  
pp. 7448-7459 ◽  
Author(s):  
Ann-Hwee Lee ◽  
Neal N. Iwakoshi ◽  
Laurie H. Glimcher
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Target Genes ◽  
Gene Profiling ◽  
Minor Role ◽  
Compensatory Mechanism ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
A Minor ◽  
Protein Response

ABSTRACT The mammalian unfolded protein response (UPR) protects the cell against the stress of misfolded proteins in the endoplasmic reticulum (ER). We have investigated here the contribution of the UPR transcription factors XBP-1, ATF6α, and ATF6β to UPR target gene expression. Gene profiling of cell lines lacking these factors yielded several XBP-1-dependent UPR target genes, all of which appear to act in the ER. These included the DnaJ/Hsp40-like genes, p58IPK, ERdj4, and HEDJ, as well as EDEM, protein disulfide isomerase-P5, and ribosome-associated membrane protein 4 (RAMP4), whereas expression of BiP was only modestly dependent on XBP-1. Surprisingly, given previous reports that enforced expression of ATF6α induced a subset of UPR target genes, cells deficient in ATF6α, ATF6β, or both had minimal defects in upregulating UPR target genes by gene profiling analysis, suggesting the presence of compensatory mechanism(s) for ATF6 in the UPR. Since cells lacking both XBP-1 and ATF6α had significantly impaired induction of select UPR target genes and ERSE reporter activation, XBP-1 and ATF6α may serve partially redundant functions. No UPR target genes that required ATF6β were identified, nor, in contrast to XBP-1 and ATF6α, did the activity of the UPRE or ERSE promoters require ATF6β, suggesting a minor role for it during the UPR. Collectively, these results suggest that the IRE1/XBP-1 pathway is required for efficient protein folding, maturation, and degradation in the ER and imply the existence of subsets of UPR target genes as defined by their dependence on XBP-1. Further, our observations suggest the existence of additional, as-yet-unknown, key regulators of the UPR.

scholarly journals Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the unfolded protein response (UPR) in models of neurodegeneration

2020 ◽  
Author(s):  
René L. Vidal ◽  
Denisse Sepulveda ◽  
Paulina Troncoso-Escudero ◽  
Paula Garcia-Huerta ◽  
Constanza Gonzalez ◽  
...  
Keyword(s):  
Gene Expression ◽  
Unfolded Protein Response ◽  
Target Genes ◽  
Cell Function ◽  
Alpha Synuclein ◽  
Protective Effects ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractAlteration to endoplasmic reticulum (ER) proteostasis is observed on a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR-target genes. Here, we designed an ATF6f-XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has stronger an effect in reducing the abnormal aggregation of mutant huntingtin and alpha-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson’s and Huntington’s disease. These results support the concept where directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

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.

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