scholarly journals Quercetin Affects Hsp70/IRE1αMediated Protection from Death Induced by Endoplasmic Reticulum Stress

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Antonello Storniolo ◽  
Marisa Raciti ◽  
Alessandra Cucina ◽  
Mariano Bizzarri ◽  
Livia Di Renzo
Keyword(s):  
Endoplasmic Reticulum ◽  
Binding Protein ◽  
Human Leukemia ◽  
Unfolded Protein ◽  
Homologous Protein ◽  
Dietary Flavonoid ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Shock Proteins ◽  
Protein Response

Relative to their normal counterparts, tumor cells generally exhibit a greater “stress phenotype” and express heat shock proteins (Hsp) that represent candidate targets for anticancer therapy. Here we investigated the role of Hsp70 in survival induced by endoplasmic reticulum (ER) stressors in human leukemia U937 cells. Quercetin, a major dietary flavonoid, or specific silencing affected the expression level of Hsp70 and did not allow the upregulation of inositol-requiring kinase 1α(IRE1α), the prototype ER stress sensor regulating the unfolded protein response (UPR), that protects the cells against the stress of misfolded proteins in the ER. The reduction of Hsp70 prevented the upregulation of immunoglobulin heavy-chain binding protein (BiP), but not of CCAAT/enhancer-binding protein-homologous protein (CHOP), and induced apoptosis. Also specific silencing of IRE1αor inhibition of its endoribonuclease activity by 4μ8c hampered the upregulation of BiP, but not of CHOP, and induced apoptosis. These results suggest that drugs affecting the Hsp70-IRE1αaxis, like quercetin, or affecting directly IRE1αmay represent an effective adjuvant antileukemia therapy.

scholarly journals Targeting Adaptive IRE1α Signaling and PLK2 in Multiple Myeloma: Possible Anti-Tumor Mechanisms of KIRA8 and Nilotinib

2020 ◽  
Vol 21 (17) ◽  
pp. 6314
Author(s):  
Yusuke Yamashita ◽  
Shuhei Morita ◽  
Hiroki Hosoi ◽  
Hiroshi Kobata ◽  
Shohei Kishimoto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Inhibitory Effect ◽  
Newly Diagnosed ◽  
Protein Kinase R ◽  
Unfolded Protein ◽  
Homologous Protein ◽  
Strong Inhibitory Effect ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Protein Response

Background: Inositol-requiring enzyme 1α (IRE1α), along with protein kinase R-like endoplasmic reticulum kinase (PERK), is a principal regulator of the unfolded protein response (UPR). Recently, the ‘mono’-specific IRE1α inhibitor, kinase-inhibiting RNase attenuator 6 (KIRA6), demonstrated a promising effect against multiple myeloma (MM). Side-stepping the clinical translation, a detailed UPR phenotype in patients with MM and the mechanisms of how KIRA8 works in MM remains unclear. Methods: We characterized UPR phenotypes in the bone marrow of patients with newly diagnosed MM. Then, in human MM cells we analyzed the possible anti-tumor mechanisms of KIRA8 and a Food and Drug Administration (FDA)-approved drug, nilotinib, which we recently identified as having a strong inhibitory effect against IRE1α activity. Finally, we performed an RNA-sequence analysis to detect key IRE1α-related molecules against MM. Results: We illustrated the dominant induction of adaptive UPR markers under IRE1α over the PERK pathway in patients with MM. In human MM cells, KIRA8 decreased cell viability and induced apoptosis, along with the induction of C/EBP homologous protein (CHOP); its combination with bortezomib exhibited more anti-myeloma effects than KIRA8 alone. Nilotinib exerted a similar effect compared with KIRA8. RNA-sequencing identified Polo-like kinase 2 (PLK2) as a KIRA8-suppressed gene. Specifically, the IRE1α overexpression induced PLK2 expression, which was decreased by KIRA8. KIRA8 and PLK2 inhibition exerted anti-myeloma effects with apoptosis induction and the regulation of cell proliferation. Finally, PLK2 was pathologically confirmed to be highly expressed in patients with MM. Conclusion: Dominant activation of adaptive IRE1α was established in patients with MM. Both KIRA8 and nilotinib exhibited anti-myeloma effects, which were enhanced by bortezomib. Adaptive IRE1α signaling and PLK2 could be potential therapeutic targets and biomarkers in MM.

scholarly journals Induction of the FK506-binding protein, FKBP13, under conditions which misfold proteins in the endoplasmic reticulum

1994 ◽  
Vol 303 (3) ◽  
pp. 705-708 ◽  
Author(s):  
K T Bush ◽  
B A Hendrickson ◽  
S K Nigam
Keyword(s):  
Endoplasmic Reticulum ◽  
Mdck Cells ◽  
Binding Protein ◽  
Significant Similarity ◽  
Fk506 Binding Protein ◽  
Unfolded Protein ◽  
Immunoglobulin Binding Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Immunoglobulin Binding

In order to determine whether the endoplasmic reticulum (ER) luminal FK506-binding protein, FKBP13, shares properties of ER molecular chaperones, MDCK cells were treated with either tunicamycin or Ca2+ ionophores. By Northern-blot analysis, tunicamycin resulted in a 2-fold rise in FKBP13 mRNA, whereas ionophores (A23187 and ionomycin) caused a more impressive rise in FKBP13 mRNA (up to 5-fold with ionomycin). Actinomycin D chase experiments in ionomycin-treated cells revealed no change in the half-life of FKBP13 mRNA, indicating that the increase in FKBP13 mRNA observed was not due to greater message stability. Moreover, sequencing of the 5′ flanking region of the gene for murine FKBP13 revealed significant similarity to similar regions in human BiP (immunoglobulin-binding protein) and the human glucose-regulated protein grp94, including a 37 bp sequence in FKBP13 with approximately 50% identity with the unfolded protein response element of the BiP gene. Together, these data suggest a role for FKBP13 in ER protein folding.

scholarly journals Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor

2005 ◽  
Vol 171 (1) ◽  
pp. 61-73 ◽  
Author(s):  
Tracie DeVries-Seimon ◽  
Yankun Li ◽  
Pin Mei Yao ◽  
Elizabeth Stone ◽  
Yibin Wang ◽  
...  
Keyword(s):  
Scavenger Receptor ◽  
Type A ◽  
Mapk Signaling ◽  
Cholesterol Trafficking ◽  
Unfolded Protein ◽  
Homologous Protein ◽  
Plaque Destabilization ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Protein Response

Macrophage death in advanced atherosclerosis promotes necrosis and plaque destabilization. A likely cause of macrophage death is accumulation of free cholesterol (FC) in the ER, leading to activation of the unfolded protein response (UPR) and C/EBP homologous protein (CHOP)–induced apoptosis. Here we show that p38 MAPK signaling is necessary for CHOP induction and apoptosis. Additionally, two other signaling pathways must cooperate with p38-CHOP to effect apoptosis. One involves the type A scavenger receptor (SRA). As evidence, FC loading by non-SRA mechanisms activates p38 and CHOP, but not apoptosis unless the SRA is engaged. The other pathway involves c-Jun NH2-terminal kinase (JNK)2, which is activated by cholesterol trafficking to the ER, but is independent of CHOP. Thus, FC-induced apoptosis requires cholesterol trafficking to the ER, which triggers p38-CHOP and JNK2, and engagement of the SRA. These findings have important implications for understanding how the UPR, MAPKs, and the SRA might conspire to cause macrophage death, lesional necrosis, and plaque destabilization in advanced atherosclerotic lesions.

scholarly journals The Drosophila metallopeptidase superdeath decouples apoptosis from the activation of the ER stress response

2019 ◽  
Author(s):  
Rebecca A.S. Palu ◽  
Clement Y. Chow
Keyword(s):  
Endoplasmic Reticulum ◽  
Drosophila Melanogaster ◽  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Membrane Bound ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACTEndoplasmic reticulum (ER) stress-induced apoptosis is a primary cause and modifier of degeneration in a number of genetic disorders. Understanding how genetic variation between individuals influences the ER stress response and subsequent activation of apoptosis could improve individualized therapies and predictions of outcomes for patients. In this study, we find that the uncharacterized, membrane-bound metallopeptidase CG14516 in Drosophila melanogaster, which we rename as SUPpressor of ER stress-induced DEATH (superdeath), plays a role in modifying ER stress-induced apoptosis. We demonstrate that loss of superdeath reduces apoptosis and degeneration in the Rh1G69D model of ER stress through the JNK signaling cascade. This effect on apoptosis occurs without altering the activation of the unfolded protein response (IRE1 and PERK), suggesting that the beneficial pro-survival effects of this response are intact. Furthermore, we show that superdeath functions epistatically upstream of CDK5, a known JNK-activated pro-apoptotic factor in this model of ER stress. We demonstrate that superdeath is not only a modifier of this particular model, but functions as a general modifier of ER stress-induced apoptosis across different tissues and ER stresses. Finally, we present evidence of Superdeath localization to the endoplasmic reticulum membrane. While similar in sequence to a number of human metallopeptidases found in the plasma membrane and ER membrane, its localization suggests that superdeath is orthologous to ERAP1/2 in humans. Together, this study provides evidence that superdeath is a link between stress in the ER and activation of cytosolic apoptotic pathways.SIGNIFICANCE STATEMENTGenetic diseases display a great deal of variability in presentation, progression, and overall outcomes. Much of this variability is caused by differences in genetic background among patients. One process that commonly modifies degenerative disease is the endoplasmic reticulum (ER) stress response. Understanding the genetic sources of variation in the ER stress response could improve individual diagnosis and treatment decisions. In this study, we characterized one such modifier in Drosophila melanogaster, the membrane-bound metallopeptidase CG14516 (superdeath). Loss of this enzyme suppresses a model of ER stress-induced degeneration by reducing cell death without altering the beneficial activation of the unfolded protein response. Our findings make superdeath and its orthologues attractive therapeutic targets in degenerative disease.

scholarly journals Enhanced Biosynthesis of Coagulation Factor VIII through Diminished Engagement of the Unfolded Protein Response

2011 ◽  
Vol 286 (27) ◽  
pp. 24451-24457 ◽  
Author(s):  
Harrison C. Brown ◽  
Bagirath Gangadharan ◽  
Christopher B. Doering
Keyword(s):  
Endoplasmic Reticulum ◽  
Factor Viii ◽  
Unfolded Protein Response ◽  
Binding Protein ◽  
Coagulation Factor ◽  
Coagulation Factor Viii ◽  
Luciferase Reporter ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Human and porcine coagulation factor VIII (fVIII) display a biosynthetic efficiency differential that is being exploited for the development of new protein and gene transfer-based therapies for hemophilia A. The cellular and/or molecular mechanism(s) responsible for this phenomenon have yet to be uncovered, although it has been temporally localized to post-translational biosynthetic steps. The unfolded protein response (UPR) is a cellular adaptation to structurally distinct (e.g. misfolded) or excess protein in the endoplasmic reticulum and is known to be induced by heterologous expression of recombinant human fVIII. Therefore, it is plausible that the biosynthetic differential between human and porcine fVIII results from differential UPR activation. In the current study, UPR induction was examined in the context of ongoing fVIII expression. UPR activation was greater during human fVIII expression when compared with porcine fVIII expression as determined by ER response element (ERSE)-luciferase reporter activity, X-box-binding protein 1 (XBP1) splicing, and immunoglobulin-binding protein (BiP) up-regulation. Immunofluorescence microscopy of fVIII expressing cells revealed that human fVIII was notably absent in the Golgi apparatus, confirming that endoplasmic reticulum to Golgi transport is rate-limiting. In contrast, a significant proportion of porcine fVIII was localized to the Golgi indicating efficient transit through the secretory pathway. Overexpression of BiP, an integral UPR protein, reduced the secretion of human fVIII by 50%, but had no effect on porcine fVIII biosynthesis. In contrast, expression of BiP shRNA increased human fVIII expression levels. The current data support the model of differential engagement of UPR by human and porcine fVIII as a non-traditional mechanism for regulation of gene product biosynthesis.

scholarly journals Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay

2021 ◽  
Author(s):  
Fatima Cairrao ◽  
Cristiana C Santos ◽  
Adrien Le Thomas ◽  
Scot Marsters ◽  
Avi Ashkenazi ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Binding Sites ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Unfolded Protein ◽  
Xbp1 Mrna ◽  
Regulatory Link ◽  
The Unfolded Protein Response ◽  
Protein Response

SUMMARYThe unfolded protein response (UPR) maintains homeostasis of the endoplasmic reticulum(ER). Residing in the ER membrane, the UPR mediator Ire1 deploys its cytoplasmic kinase-endoribonuclease domain to activate the key UPR transcription factor Xbp1 through non-conventional splicing of Xbp1 mRNA. Ire1 also degrades diverse ER-targeted mRNAs through regulated Ire1-dependent decay (RIDD), but how it spares Xbp1 mRNA from this decay is unknown. We identified binding sites for the RNA-binding protein Pumilio in the 3’UTR Drosophila Xbp1. In the developing Drosophila eye, Pumilio bound both the Xbp1unspliced and Xbp1spliced mRNAs, but only Xbp1spliced was stabilized by Pumilio. Furthermore, Pumilio displayed Ire1 kinase-dependent phosphorylation during ER stress, which was required for its stabilization of Xbp1spliced. Human IRE1 could directly phosphorylate Pumilio, and phosphorylated Pumilio protected Xbp1spliced mRNA against RIDD. Thus, Ire1-mediated phosphorylation enables Pumilio to shield Xbp1spliced from RIDD. These results uncover an important and unexpected regulatory link between an RNA-binding protein and the UPR.

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