scholarly journals Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response

2009 ◽  
Vol 424 (2) ◽  
pp. 273-283 ◽  
Author(s):  
Stefka D. Spassieva ◽  
Thomas D. Mullen ◽  
Danyelle M. Townsend ◽  
Lina M. Obeid
Keyword(s):  
Unfolded Protein Response ◽  
Stress Responses ◽  
Apoptotic Cell ◽  
Sphingolipid Metabolism ◽  
Ceramide Synthase ◽  
Down Regulation ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Long Chain

Ceramide metabolism has come under recent scrutiny because of its role in cellular stress responses. CerS2 (ceramide synthase 2) is one of the six mammalian isoforms of ceramide synthase and is responsible for the synthesis of VLC (very-long-chain) ceramides, e.g. C24, C24:1. To study the role of CerS2 in ceramide metabolism and cellular homoeostasis, we down-regulated CerS2 using siRNA (small interfering RNA) and examined several aspects of sphingolipid metabolism and cell stress responses. CerS2 down-regulation had a broad effect on ceramide homoeostasis, not just on VLC ceramides. Surprisingly, CerS2 down-regulation resulted in significantly increased LC (long-chain) ceramides, e.g. C14, C16, and our results suggested that the increase was due to a ceramide synthase-independent mechanism. CerS2-down-regulation-induced LC ceramide accumulation resulted in growth arrest which was not accompanied by apoptotic cell death. Instead, cells remained viable, showing induction of autophagy and activation of PERK [PKR (double-stranded-RNA-dependent protein kinase)-like endoplasmic reticulum kinase] and IRE1 (inositol-requiring 1) pathways [the latter indicating activation of the UPR (unfolded protein response)].

scholarly journals Herpesviruses and the Unfolded Protein Response

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 17 ◽  
Author(s):  
Benjamin P. Johnston ◽  
Craig McCormick
Keyword(s):  
Unfolded Protein Response ◽  
Stress Responses ◽  
Immune Surveillance ◽  
Lytic Replication ◽  
Glycoprotein Synthesis ◽  
Unfolded Protein ◽  
Transcriptional Reprogramming ◽  
Molecular Events ◽  
The Unfolded Protein Response ◽  
Protein Response

Herpesviruses usurp cellular stress responses to promote viral replication and avoid immune surveillance. The unfolded protein response (UPR) is a conserved stress response that is activated when the protein load in the ER exceeds folding capacity and misfolded proteins accumulate. The UPR aims to restore protein homeostasis through translational and transcriptional reprogramming; if homeostasis cannot be restored, the UPR switches from “helper” to “executioner”, triggering apoptosis. It is thought that the burst of herpesvirus glycoprotein synthesis during lytic replication causes ER stress, and that these viruses may have evolved mechanisms to manage UPR signaling to create an optimal niche for replication. The past decade has seen considerable progress in understanding how herpesviruses reprogram the UPR. Here we provide an overview of the molecular events of UPR activation, signaling and transcriptional outputs, and highlight key evidence that herpesviruses hijack the UPR to aid infection.

scholarly journals Opposing unfolded-protein-response signals converge on death receptor 5 to control apoptosis

Science ◽  
2014 ◽  
Vol 345 (6192) ◽  
pp. 98-101 ◽  
Author(s):  
Min Lu ◽  
David A. Lawrence ◽  
Scot Marsters ◽  
Diego Acosta-Alvear ◽  
Philipp Kimmig ◽  
...  
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Cell Fate ◽  
Apoptotic Cell ◽  
Death Receptor ◽  
Caspase 8 ◽  
Death Receptor 5 ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Protein folding by the endoplasmic reticulum (ER) is physiologically critical; its disruption causes ER stress and augments disease. ER stress activates the unfolded protein response (UPR) to restore homeostasis. If stress persists, the UPR induces apoptotic cell death, but the mechanisms remain elusive. Here, we report that unmitigated ER stress promoted apoptosis through cell-autonomous, UPR-controlled activation of death receptor 5 (DR5). ER stressors induced DR5 transcription via the UPR mediator CHOP; however, the UPR sensor IRE1α transiently catalyzed DR5 mRNA decay, which allowed time for adaptation. Persistent ER stress built up intracellular DR5 protein, driving ligand-independent DR5 activation and apoptosis engagement via caspase-8. Thus, DR5 integrates opposing UPR signals to couple ER stress and apoptotic cell fate.

scholarly journals Regulation of the unfolded protein response by noncoding RNA

2017 ◽  
Vol 313 (3) ◽  
pp. C243-C254 ◽  
Author(s):  
Mari McMahon ◽  
Afshin Samali ◽  
Eric Chevet
Keyword(s):  
Unfolded Protein Response ◽  
Stress Responses ◽  
Noncoding Rna ◽  
Noncoding Rnas ◽  
Small Noncoding Rna ◽  
Downstream Signaling ◽  
Unfolded Protein ◽  
Cell Death Mechanisms ◽  
The Unfolded Protein Response ◽  
Protein Response

Cells are exposed to various intrinsic and extrinsic stresses in both physiological and pathological conditions. To adapt to those conditions, cells have evolved various mechanisms to cope with the disturbances in protein demand, largely through the unfolded protein response (UPR) in the endoplasmic reticulum (ER), but also through the integrated stress response (ISR). Both responses initiate downstream signaling to transcription factors that, in turn, trigger adaptive programs and/or in the case of prolonged stress, cell death mechanisms. Recently, noncoding RNAs, including microRNA and long noncoding RNA, have emerged as key players in the stress responses. These noncoding RNAs act as both regulators and effectors of the UPR and fine-tune the output of the stress signaling pathways. Although much is known about the UPR and the cross talk that exists between pathways, the contribution of small noncoding RNA has not been fully assessed. Herein we bring together and review the current known functions of noncoding RNA in regulating adaptive pathways in both physiological and pathophysiological conditions, illustrating how they operate within the known UPR functions and contribute to diverse cellular outcomes.

scholarly journals Translational and posttranslational regulation of XIAP by eIF2α and ATF4 promotes ER stress–induced cell death during the unfolded protein response

2014 ◽  
Vol 25 (9) ◽  
pp. 1411-1420 ◽  
Author(s):  
Nobuhiko Hiramatsu ◽  
Carissa Messah ◽  
Jaeseok Han ◽  
Matthew M. LaVail ◽  
Randal J. Kaufman ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Protein Misfolding ◽  
Down Regulation ◽  
Unfolded Protein ◽  
Activity Loss ◽  
The Unfolded Protein Response ◽  
Protein Response

Endoplasmic reticulum (ER) protein misfolding activates the unfolded protein response (UPR) to help cells cope with ER stress. If ER homeostasis is not restored, UPR promotes cell death. The mechanisms of UPR-mediated cell death are poorly understood. The PKR-like endoplasmic reticulum kinase (PERK) arm of the UPR is implicated in ER stress–induced cell death, in part through up-regulation of proapoptotic CCAAT/enhancer binding protein homologous protein (CHOP). Chop−/− cells are partially resistant to ER stress–induced cell death, and CHOP overexpression alone does not induce cell death. These findings suggest that additional mechanisms regulate cell death downstream of PERK. Here we find dramatic suppression of antiapoptosis XIAP proteins in response to chronic ER stress. We find that PERK down-regulates XIAP synthesis through eIF2α and promotes XIAP degradation through ATF4. Of interest, PERK's down-regulation of XIAP occurs independently of CHOP activity. Loss of XIAP leads to increased cell death, whereas XIAP overexpression significantly enhances resistance to ER stress–induced cell death, even in the absence of CHOP. Our findings define a novel signaling circuit between PERK and XIAP that operates in parallel with PERK to CHOP induction to influence cell survival during ER stress. We propose a “two-hit” model of ER stress–induced cell death involving concomitant CHOP up-regulation and XIAP down-regulation both induced by PERK.

scholarly journals Stress Management: Death Receptor Signalling and Cross-Talks with the Unfolded Protein Response in Cancer

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1113 ◽  
Author(s):  
Elodie Lafont
Keyword(s):  
Unfolded Protein Response ◽  
Stress Responses ◽  
Tumour Progression ◽  
Death Receptor ◽  
Tumour Cells ◽  
Unfolded Protein ◽  
Extrinsic Cues ◽  
Molecular Determinants ◽  
The Unfolded Protein Response ◽  
Protein Response

Throughout tumour progression, tumour cells are exposed to various intense cellular stress conditions owing to intrinsic and extrinsic cues, to which some cells are remarkably able to adapt. Death Receptor (DR) signalling and the Unfolded Protein Response (UPR) are two stress responses that both regulate a plethora of outcomes, ranging from proliferation, differentiation, migration, cytokine production to the induction of cell death. Both signallings are major modulators of physiological tissue homeostasis and their dysregulation is involved in tumorigenesis and the metastastic process. The molecular determinants of the control between the different cellular outcomes induced by DR signalling and the UPR in tumour cells and their stroma and their consequences on tumorigenesis are starting to be unravelled. Herein, I summarize the main steps of DR signalling in relation to its cellular and pathophysiological roles in cancer. I then highlight how the UPR and DR signalling control common cellular outcomes and also cross-talk, providing potential opportunities to further understand the development of malignancies.

Endoplasmic Reticulum Stress: Signaling the Unfolded Protein Response

Physiology ◽  
2007 ◽  
Vol 22 (3) ◽  
pp. 193-201 ◽  
Author(s):  
Elida Lai ◽  
Tracy Teodoro ◽  
Allen Volchuk
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Apoptotic Cell ◽  
Signaling Cascades ◽  
Stress Signaling ◽  
Apoptosis Induction ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

The endoplasmic reticulum (ER) is the cellular site of newly synthesized secretory and membrane proteins. Such proteins must be properly folded and posttranslationally modified before exit from the organelle. Proper protein folding and modification requires molecular chaperone proteins as well as an ER environment conducive for these reactions. When ER lumenal conditions are altered or chaperone capacity is overwhelmed, the cell activates signaling cascades that attempt to deal with the altered conditions and restore a favorable folding environment. Such alterations are referred to as ER stress, and the response activated is the unfolded protein response (UPR). When the UPR is perturbed or not sufficient to deal with the stress conditions, apoptotic cell death is initiated. This review will examine UPR signaling that results in cell protective responses, as well as the mechanisms leading to apoptosis induction, which can lead to pathological states due to chronic ER stress.

scholarly journals The unfolded protein response and its potential role in Huntington ́s disease elucidated by a systems biology approach

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 103 ◽  
Author(s):  
Ravi Kiran Reddy Kalathur ◽  
Joaquin Giner-Lamia ◽  
Susana Machado ◽  
Kameshwar R S Ayasolla ◽  
Matthias E. Futschik
Keyword(s):  
Cell Death ◽  
Unfolded Protein Response ◽  
Potential Role ◽  
Apoptotic Cell ◽  
Fatal Outcome ◽  
Neuronal Cell ◽  
Misfolded Proteins ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Huntington ́s disease (HD) is a progressive, neurodegenerative disease with a fatal outcome. Although the disease-causing gene (huntingtin) has been known for over 20 years, the exact mechanisms leading to neuronal cell death are still controversial. One potential mechanism contributing to the massive loss of neurons observed in the brain of HD patients could be the unfolded protein response (UPR) activated by accumulation of misfolded proteins in the endoplasmic reticulum (ER). As an adaptive response to counter-balance accumulation of un- or misfolded proteins, the UPR upregulates transcription of chaperones, temporarily attenuates new translation, and activates protein degradation via the proteasome. However, persistent ER stress and an activated UPR can also cause apoptotic cell death. Although different studies have indicated a role for the UPR in HD, the evidence remains inconclusive. Here, we present extensive bioinformatic analyses that revealed UPR activation in different experimental HD models based on transcriptomic data. Accordingly, we have identified 58 genes, including RAB5A, HMGB1, CTNNB1, DNM1, TUBB, TSG101, EEF2, DYNC1H1 and SLC12A5 that provide a potential link between UPR and HD. To further elucidate the potential role of UPR as a disease-relevant process, we examined its connection to apoptosis based on molecular interaction data, and identified a set of 40 genes including ADD1, HSP90B1, IKBKB, IKBKG, RPS3A and LMNB1, which seem to be at the crossroads between these two important cellular processes.

Antioxidants Improve Factor VIII Secretion in the Liver by Preventing Oxidative Stress, Activation of the Unfolded Protein Response, and Apoptosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 197-197
Author(s):  
Jyoti D. Malhotra ◽  
Kezhong Zhang ◽  
Hongzi Miao ◽  
Steven W. Pipe ◽  
Randal J. Kaufman
Keyword(s):  
Oxidative Stress ◽  
Factor Viii ◽  
Unfolded Protein Response ◽  
Stress Responses ◽  
Factor V ◽  
Dna Encoding ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Factor V (FV) and Factor VIII (FVIII) are homologous glycoproteins that provide essential functions in hemostasis. Previous studies demonstrated that compared to FV, the FVIII polypeptide folds inefficiently, accumulates in the endoplasmic reticulum (ER) and activates the Unfolded Protein Response (UPR). The UPR, mediated by the proximal sensors PERK and IRE1, is a signaling pathway leading to either adaptive survival or apoptotic demise upon accumulation of unfolded proteins in the ER. Here we show that FVIII expression in hepatocytes in vivo mediated by hydrodynamic tail-vein injection of plasmid DNA into fviii −/ − mice produces between 0.5 to 1.0 Unit/ml of FVIII in the plasma. This level of FVIII expression activated PERK and IRE1 to signal the UPR and induced both markers of oxidative stress and apoptosis in hepatocytes. In contrast, injection of DNA encoding either FV or a FVIII molecule engineered for improved secretion did not induce oxidative stress, activate the UPR or induce apoptosis. Gene expression analysis demonstrated that FVIII expression induced expression of the proapoptotic transcription factor CHOP. Injection of FVIII expression plasmids into chop−/ − mice did not induce oxidative stress or apoptosis, indicating that these stress responses require CHOP. Feeding of mice with the lipid soluble antioxidant, butylated hydroxy anisole (BHA), reduced oxidative stress and apoptosis and increased expression of FVIII in the plasma, demonstrating a pivotal role of oxidative stress in limiting FVIII expression and triggering apoptosis. Finally, overexpression of the anti-apoptotic protein Bcl2 also significantly suppressed oxidative stress and apoptosis and increased FVIII expression. The results demonstrate that 1) misfolding of an ER luminal protein, FVIII, is sufficient to induce oxidative stress and apoptosis in vivo, 2) oxidative stress limits protein secretion and activates apoptosis through a mechanism that requires CHOP, and 3) intervention to prevent oxidative stress by antioxidant feeding or Bcl2 overexpression preserves ER function, improves secretion and prevents apoptosis. The findings raise the possibility to treat diseases of protein misfolding, such as certain mutations that cause hemophilia A, by treatment with antioxidants.

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