Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 1. An overview

2014 ◽  
Vol 307 (7) ◽  
pp. C582-C594 ◽  
Author(s):  
Estefanie Dufey ◽  
Denisse Sepúlveda ◽  
Diego Rojas-Rivera ◽  
Claudio Hetz
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Fate ◽  
Target Genes ◽  
Physiological Role ◽  
Protein Translation ◽  
Fine Tuning ◽  
Secretory Cells ◽  
Cellular Mechanisms ◽  
Physiological Outcomes ◽  
The Unfolded Protein Response

Increased demand on the protein folding capacity of the endoplasmic reticulum (ER) engages an adaptive reaction known as the unfolded protein response (UPR). The UPR regulates protein translation and the expression of numerous target genes that contribute to restore ER homeostasis or induce apoptosis of irreversibly damaged cells. UPR signaling is highly regulated and dynamic and integrates information about the type, intensity, and duration of the stress stimuli, thereby determining cell fate. Recent advances highlight novel physiological outcomes of the UPR beyond specialized secretory cells, particularly in innate immunity, metabolism, and cell differentiation. Here we discuss studies on the fine-tuning of the UPR and its physiological role in diverse organs and diseases.

scholarly journals A Role for the DnaJ Homologue Scj1p in Protein Folding in the Yeast Endoplasmic Reticulum

1998 ◽  
Vol 143 (4) ◽  
pp. 921-933 ◽  
Author(s):  
Susana Silberstein ◽  
Gabriel Schlenstedt ◽  
Pam A. Silver ◽  
Reid Gilmore
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Physiological Role ◽  
Carboxypeptidase Y ◽  
Reporter Protein ◽  
Unfolded Protein ◽  
A Cell ◽  
The Unfolded Protein Response ◽  
Protein Response

Members of the eukaryotic heat shock protein 70 family (Hsp70s) are regulated by protein cofactors that contain domains homologous to bacterial DnaJ. Of the three DnaJ homologues in the yeast rough endoplasmic reticulum (RER; Scj1p, Sec63p, and Jem1p), Scj1p is most closely related to DnaJ, hence it is a probable cofactor for Kar2p, the major Hsp70 in the yeast RER. However, the physiological role of Scj1p has remained obscure due to the lack of an obvious defect in Kar2p-mediated pathways in scj1 null mutants. Here, we show that the Δscj1 mutant is hypersensitive to tunicamycin or mutations that reduce N-linked glycosylation of proteins. Although maturation of glycosylated carboxypeptidase Y occurs with wild-type kinetics in Δscj1 cells, the transport rate for an unglycosylated mutant carboxypeptidase Y (CPY) is markedly reduced. Loss of Scj1p induces the unfolded protein response pathway, and results in a cell wall defect when combined with an oligosaccharyltransferase mutation. The combined loss of both Scj1p and Jem1p exaggerates the sensitivity to hypoglycosylation stress, leads to further induction of the unfolded protein response pathway, and drastically delays maturation of an unglycosylated reporter protein in the RER. We propose that the major role for Scj1p is to cooperate with Kar2p to mediate maturation of proteins in the RER lumen.

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 Stressed: The Unfolded Protein Response in T Cell Development, Activation, and Function

2019 ◽  
Vol 20 (7) ◽  
pp. 1792 ◽  
Author(s):  
Kyeorda Kemp ◽  
Cody Poe
Keyword(s):  
Endoplasmic Reticulum ◽  
T Cell ◽  
Unfolded Protein Response ◽  
T Cell Development ◽  
Cell Development ◽  
Secretory Cells ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response

The unfolded protein response (UPR) is a highly conserved pathway that allows cells to respond to stress in the endoplasmic reticulum caused by an accumulation of misfolded and unfolded protein. This is of great importance to secretory cells because, in order for proteins to traffic from the endoplasmic reticulum (ER), they need to be folded appropriately. While a wealth of literature has implicated UPR in immune responses, less attention has been given to the role of UPR in T cell development and function. This review discusses the importance of UPR in T cell development, homeostasis, activation, and effector functions. We also speculate about how UPR may be manipulated in T cells to ameliorate pathologies.

scholarly journals Endoplasmic reticulum stress regulation of the Kar2p/BiP chaperone alleviates proteotoxicity via dual degradation pathways

2012 ◽  
Vol 23 (4) ◽  
pp. 630-641 ◽  
Author(s):  
Chia-Ling Hsu ◽  
Rupali Prasad ◽  
Christie Blackman ◽  
Davis T. W. Ng
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Target Genes ◽  
Regulatory Element ◽  
Unfolded Protein ◽  
Single Target ◽  
Transcriptional Regulatory ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Stress Activation

The unfolded protein response (UPR) monitors and maintains protein homeostasis in the endoplasmic reticulum (ER). In budding yeast, the UPR is a transcriptional regulatory pathway that is quiescent under normal conditions. Under conditions of acute ER stress, activation of UPR targets is essential for cell viability. How individual target genes contribute to stress tolerance is unclear. Uncovering these roles is hampered because most targets also play important functions in the absence of stress. To differentiate stress-specific roles from everyday functions, a single target gene was uncoupled from UPR control by eliminating its UPR-specific regulatory element. Through this approach, the UPR remains intact, aside from its inability to induce the designated target. Applying the strategy to the major ER chaperone Kar2p/BiP revealed the physiological function of increasing its cellular concentration. Despite hundreds of target genes under UPR control, we show that activation of KAR2 is indispensable to alleviate some forms of ER stress. Specifically, activation is essential to dispose misfolded proteins that are otherwise toxic. Surprisingly, induced BiP/Kar2p molecules are dedicated to alleviating stress. The inability to induce KAR2 under stress had no effect on its known housekeeping functions.

scholarly journals Specificity in endoplasmic reticulum-stress signaling in yeast entails a step-wise engagement of HAC1 mRNA to clusters of the stress sensor Ire1

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Eelco van Anken ◽  
David Pincus ◽  
Scott Coyle ◽  
Tomás Aragón ◽  
Christof Osman ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Target Genes ◽  
Transmembrane Domain ◽  
Transcription Activator ◽  
Stress Sensor ◽  
Unfolded Protein ◽  
Oligomeric Assembly ◽  
The Unfolded Protein Response ◽  
Linker Domain

Insufficient protein-folding capacity in the endoplasmic reticulum (ER) induces the unfolded protein response (UPR). In the ER lumen, accumulation of unfolded proteins activates the transmembrane ER-stress sensor Ire1 and drives its oligomerization. In the cytosol, Ire1 recruits HAC1 mRNA, mediating its non-conventional splicing. The spliced mRNA is translated into Hac1, the key transcription activator of UPR target genes that mitigate ER-stress. In this study, we report that oligomeric assembly of the ER-lumenal domain is sufficient to drive Ire1 clustering. Clustering facilitates Ire1's cytosolic oligomeric assembly and HAC1 mRNA docking onto a positively charged motif in Ire1's cytosolic linker domain that tethers the kinase/RNase to the transmembrane domain. By the use of a synthetic bypass, we demonstrate that mRNA docking per se is a pre-requisite for initiating Ire1's RNase activity and, hence, splicing. We posit that such step-wise engagement between Ire1 and its mRNA substrate contributes to selectivity and efficiency in UPR signaling.

scholarly journals Structural and Functional Significance of the Endoplasmic Reticulum Unfolded Protein Response Transducers and Chaperones at the Mitochondria–ER Contacts: A Cancer Perspective

2021 ◽  
Vol 9 ◽  
Author(s):  
Giuseppina Amodio ◽  
Valentina Pagliara ◽  
Ornella Moltedo ◽  
Paolo Remondelli
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Cell Fate ◽  
Tumor Development ◽  
Unfolded Protein ◽  
Mitochondria Dynamics ◽  
Fate Decision ◽  
The Unfolded Protein Response ◽  
Almost All ◽  
Protein Response

In the last decades, the endoplasmic reticulum (ER) has emerged as a key coordinator of cellular homeostasis, thanks to its physical interconnection to almost all intracellular organelles. In particular, an intense and mutual crosstalk between the ER and mitochondria occurs at the mitochondria–ER contacts (MERCs). MERCs ensure a fine-tuned regulation of fundamental cellular processes, involving cell fate decision, mitochondria dynamics, metabolism, and proteostasis, which plays a pivotal role in the tumorigenesis and therapeutic response of cancer cells. Intriguingly, recent studies have shown that different components of the unfolded protein response (UPR) machinery, including PERK, IRE1α, and ER chaperones, localize at MERCs. These proteins appear to exhibit multifaceted roles that expand beyond protein folding and UPR transduction and are often related to the control of calcium fluxes to the mitochondria, thus acquiring relevance to cell survival and death. In this review, we highlight the novel functions played by PERK, IRE1α, and ER chaperones at MERCs focusing on their impact on tumor development.

scholarly journals Endoplasmic Reticulum Stress: Its Role in Disease and Novel Prospects for Therapy

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-26 ◽  
Author(s):  
Axel H. Schönthal
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Er Stress ◽  
Prescription Drugs ◽  
Pancreatic Beta Cells ◽  
Cell Function ◽  
Tumor Cell Death ◽  
Cellular Mechanisms ◽  
Pharmacological Agents ◽  
The Unfolded Protein Response

The endoplasmic reticulum (ER) is a multifunctional organelle required for lipid biosynthesis, calcium storage, and protein folding and processing. A number of physiological and pathological conditions, as well as a variety of pharmacological agents, are able to disturb proper ER function and thereby cause ER stress, which severely impairs protein folding and therefore poses the risk of proteotoxicity. Specific triggers for ER stress include, for example, particular intracellular alterations (e.g., calcium or redox imbalances), certain microenvironmental conditions (e.g., hypoglycemia, hypoxia, and acidosis), high-fat and high-sugar diet, a variety of natural compounds (e.g., thapsigargin, tunicamycin, and geldanamycin), and several prescription drugs (e.g., bortezomib/Velcade, celecoxib/Celebrex, and nelfinavir/Viracept). The cell reacts to ER stress by initiating a defensive process, called the unfolded protein response (UPR), which is comprised of cellular mechanisms aimed at adaptation and safeguarding cellular survival or, in cases of excessively severe stress, at initiation of apoptosis and elimination of the faulty cell. In recent years, this dichotomic stress response system has been linked to several human diseases, and efforts are underway to develop approaches to exploit ER stress mechanisms for therapy. For example, obesity and type 2 diabetes have been linked to ER stress-induced failure of insulin-producing pancreatic beta cells, and current research efforts are aimed at developing drugs that ameliorate cellular stress and thereby protect beta cell function. Other studies seek to pharmacologically aggravate chronic ER stress in cancer cells in order to enhance apoptosis and achieve tumor cell death. In the following, these principles will be presented and discussed.

scholarly journals Regulation of the unfolded protein response by microRNAs

2013 ◽  
Vol 18 (4) ◽  
Author(s):  
Sylwia Bartoszewska ◽  
Kinga Kochan ◽  
Piotr Madanecki ◽  
Arkadiusz Piotrowski ◽  
Renata Ochocka ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Unfolded Protein Response ◽  
Potential Role ◽  
Recovery Phase ◽  
Cellular Mechanisms ◽  
Unfolded Protein ◽  
Critical Components ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe unfolded protein response (UPR) is an adaptive response to the stress that is caused by an accumulation of misfolded proteins in the lumen of the endoplasmic reticulum (ER). It is an important component of cellular homeostasis. During ER stress, the UPR increases the protein-folding capacity of the endoplasmic reticulum to relieve the stress. Failure to recover leads to apoptosis. Specific cellular mechanisms are required for the cellular recovery phase after UPR activation. Using bioinformatics tools, we identified a number of microRNAs that are predicted to decrease the mRNA expression levels for a number of critical components of the UPR. In this review, we discuss the potential role of microRNAs as key regulators of this pathway and describe how microRNAs may play an essential role in turning off the UPR after the stress has subsided.

scholarly journals Intracellular Communication among Morphogen Signaling Pathways during Vertebrate Body Plan Formation

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 341
Author(s):  
Kimiko Takebayashi-Suzuki ◽  
Atsushi Suzuki
Keyword(s):  
Growth Factor ◽  
Signaling Pathways ◽  
Cell Fate ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Body Plan ◽  
The Body ◽  
Fine Tuning ◽  
Axis Formation

During embryonic development in vertebrates, morphogens play an important role in cell fate determination and morphogenesis. Bone morphogenetic proteins (BMPs) belonging to the transforming growth factor-β (TGF-β) family control the dorsal–ventral (DV) patterning of embryos, whereas other morphogens such as fibroblast growth factor (FGF), Wnt family members, and retinoic acid (RA) regulate the formation of the anterior–posterior (AP) axis. Activation of morphogen signaling results in changes in the expression of target genes including transcription factors that direct cell fate along the body axes. To ensure the correct establishment of the body plan, the processes of DV and AP axis formation must be linked and coordinately regulated by a fine-tuning of morphogen signaling. In this review, we focus on the interplay of various intracellular regulatory mechanisms and discuss how communication among morphogen signaling pathways modulates body axis formation in vertebrate embryos.

scholarly journals Activation of endoplasmic reticulum stress via clustering of inner nuclear membrane proteins

2021 ◽  
Author(s):  
Sandra Vidak ◽  
Leonid A. Serebryannyy ◽  
Tom Misteli
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Nuclear Membrane ◽  
Premature Aging ◽  
Cellular Mechanisms ◽  
Inner Nuclear Membrane ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Hutchinson Gilford Progeria Syndrome

One of the major cellular mechanisms to ensure protein homeostasis is the endoplasmic reticulum (ER) stress response. This pathway is typically triggered by accumulation of misfolded proteins in the ER lumen. Here we describe activation of ER stress via protein aggregation in the cell nucleus. We find in the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) activation of ER stress due to the aggregation of the diseases-causing progerin protein at the nuclear envelope. The presence of nucleoplasmic protein aggregates is sensed and signaled to the ER lumen via immobilization and clustering of the inner nuclear membrane protein SUN2, leading to activation of the Unfolded Protein Response (UPR). These results identify a nuclear trigger of ER stress and they provide insight into the molecular disease mechanisms of HGPS.

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