scholarly journals Information processing by endoplasmic reticulum stress sensors

2019 ◽  
Vol 16 (158) ◽  
pp. 20190288
Author(s):  
Wylie Stroberg ◽  
Justin Eilertsen ◽  
Santiago Schnell
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Unfolded Proteins ◽  
Sensing Mechanism ◽  
Signalling Molecules ◽  
Unfolded Protein ◽  
Sensor Control ◽  
Stressed Cells ◽  
Stress Sensing ◽  
The Unfolded Protein Response

The unfolded protein response (UPR) is a collection of cellular feedback mechanisms that seek to maintain protein folding homeostasis in the endoplasmic reticulum (ER). When the ER is ‘stressed’, through either high protein folding demand or undersupply of chaperones and foldases, stress sensing proteins in the ER membrane initiate the UPR. Recently, experiments have indicated that these signalling molecules detect stress by being both sequestered by free chaperones and activated by free unfolded proteins. However, it remains unclear what advantage this bidirectional sensor control offers stressed cells. Here, we show that combining positive regulation of sensor activity by unfolded proteins with negative regulation by chaperones allows the sensor to make a more informative measurement of ER stress. The increase in the information capacity of the combined sensing mechanism stems from stretching of the active range of the sensor, at the cost of increased uncertainty due to the integration of multiple signals. These results provide a possible rationale for the evolution of the observed stress-sensing mechanism.

scholarly journals Information processing by endoplasmic reticulum stress sensors

2019 ◽  
Author(s):  
Wylie Stroberg ◽  
Justin Eilertsen ◽  
Santiago Schnell
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Unfolded Proteins ◽  
Sensing Mechanism ◽  
Unfolded Protein ◽  
Sensor Control ◽  
Stressed Cells ◽  
Stress Sensing ◽  
The Unfolded Protein Response ◽  
The Cost

AbstractThe unfolded protein response (UPR) is a collection of cellular feedback mechanisms that seek to maintain protein folding homeostasis in the endoplasmic reticulum (ER). When the ER is “stressed”, either through high protein folding demand or undersupply of chaperones and foldases, stress sensing proteins in the ER membrane initiate the UPR. Recently, experiments have indicated that these signaling molecules detect stress by being both sequestered by free chaperones and activated by free unfolded proteins. However, it remains unclear what advantage this bidirectional sensor control offers stressed cells. Here, we show that combining positive regulation of sensor activity by unfolded proteins with negative regulation by chaperones allows the sensor to make a more informative measurement of ER stress. The increase in the information capacity of the combined sensing mechanism stems from stretching of the active range of the sensor, at the cost of increased uncertainty due to the integration of multiple signals. These results provide a possible rationale for the evolution of the observed stress sensing mechanism.

scholarly journals Cadmium impairs protein folding in the endoplasmic reticulum and induces the unfolded protein response

2016 ◽  
Vol 16 (5) ◽  
pp. fow049 ◽  
Author(s):  
Quynh Giang Le ◽  
Yuki Ishiwata-Kimata ◽  
Kenji Kohno ◽  
Yukio Kimata
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

scholarly journals Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Nicholas R Guydosh ◽  
Philipp Kimmig ◽  
Peter Walter ◽  
Rachel Green
Keyword(s):  
Endoplasmic Reticulum ◽  
Critical Role ◽  
Mrna Degradation ◽  
Ribosome Profiling ◽  
Unfolded Protein ◽  
Selective Degradation ◽  
Stressed Cells ◽  
Novel Target ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response (UPR) monitors and adjusts the protein folding capacity of the endoplasmic reticulum (ER). In S. pombe, the ER membrane-resident kinase/endoribonuclease Ire1 utilizes a mechanism of selective degradation of ER-bound mRNAs (RIDD) to maintain homeostasis. We used a genetic screen to identify factors critical to the Ire1-mediated UPR and found several proteins, Dom34, Hbs1 and Ski complex subunits, previously implicated in ribosome rescue and mRNA no-go-decay (NGD). Ribosome profiling in ER-stressed cells lacking these factors revealed that Ire1-mediated cleavage of ER-associated mRNAs results in ribosome stalling and mRNA degradation. Stalled ribosomes iteratively served as a ruler to template precise, regularly spaced upstream mRNA cleavage events. This clear signature uncovered hundreds of novel target mRNAs. Our results reveal that the UPR in S. pombe executes RIDD in an intricate interplay between Ire1, translation, and the NGD pathway, and establish a critical role for NGD in maintaining ER homeostasis.

scholarly journals Endoplasmic Reticulum Stress and Lipid Metabolism: Mechanisms and Therapeutic Potential

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Sana Basseri ◽  
Richard C. Austin
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Lipid Metabolism ◽  
Er Stress ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Signal Transduction Pathway ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent

The endoplasmic reticulum (ER) plays a crucial role in protein folding, assembly, and secretion. Disruption of ER homeostasis may lead to accumulation of misfolded or unfolded proteins in the ER lumen, a condition referred to as ER stress. In response to ER stress, a signal transduction pathway known as the unfolded protein response (UPR) is activated. UPR activation allows the cell to cope with an increased protein-folding demand on the ER. Recent studies have shown that ER stress/UPR activation plays a critical role in lipid metabolism and homeostasis. ER-stress-dependent dysregulation of lipid metabolism may lead to dyslipidemia, insulin resistance, cardiovascular disease, type 2 diabetes, and obesity. In this paper, we examine recent findings illustrating the important role ER stress/UPR signalling pathways play in regulation of lipid metabolism, and how they may lead to dysregulation of lipid homeostasis.

scholarly journals Caspase-mediated cleavage of IRE1 controls apoptotic cell commitment during endoplasmic reticulum stress

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Anna Shemorry ◽  
Jonathan M Harnoss ◽  
Ofer Guttman ◽  
Scot A Marsters ◽  
László G Kőműves ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Apoptotic Cell ◽  
Leukemia Cell ◽  
Unfolded Protein ◽  
Proapoptotic Protein ◽  
Stress Sensing ◽  
The Unfolded Protein Response ◽  
Cell Commitment ◽  
Protein Response

Upon detecting endoplasmic reticulum (ER) stress, the unfolded protein response (UPR) orchestrates adaptive cellular changes to reestablish homeostasis. If stress resolution fails, the UPR commits the cell to apoptotic death. Here we show that in hematopoietic cells, including multiple myeloma (MM), lymphoma, and leukemia cell lines, ER stress leads to caspase-mediated cleavage of the key UPR sensor IRE1 within its cytoplasmic linker region, generating a stable IRE1 fragment comprising the ER-lumenal domain and transmembrane segment (LDTM). This cleavage uncouples the stress-sensing and signaling domains of IRE1, attenuating its activation upon ER perturbation. Surprisingly, LDTM exerts negative feedback over apoptotic signaling by inhibiting recruitment of the key proapoptotic protein BAX to mitochondria. Furthermore, ectopic LDTM expression enhances xenograft growth of MM tumors in mice. These results uncover an unexpected mechanism of cross-regulation between the apoptotic caspase machinery and the UPR, which has biologically significant consequences for cell survival under ER stress.

scholarly journals An unfolded protein-induced conformational switch activates mammalian IRE1

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
G Elif Karagöz ◽  
Diego Acosta-Alvear ◽  
Hieu T Nguyen ◽  
Crystal P Lee ◽  
Feixia Chu ◽  
...  
Keyword(s):  
Peptide Binding ◽  
Common Mechanism ◽  
Unfolded Proteins ◽  
Conformational Switch ◽  
Allosteric Coupling ◽  
Unfolded Protein ◽  
Stress Sensing ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Lumenal Domain

The unfolded protein response (UPR) adjusts the cell’s protein folding capacity in the endoplasmic reticulum (ER) according to need. IRE1 is the most conserved UPR sensor in eukaryotic cells. It has remained controversial, however, whether mammalian and yeast IRE1 use a common mechanism for ER stress sensing. Here, we show that similar to yeast, human IRE1α’s ER-lumenal domain (hIRE1α LD) binds peptides with a characteristic amino acid bias. Peptides and unfolded proteins bind to hIRE1α LD’s MHC-like groove and induce allosteric changes that lead to its oligomerization. Mutation of a hydrophobic patch at the oligomerization interface decoupled peptide binding to hIRE1α LD from its oligomerization, yet retained peptide-induced allosteric coupling within the domain. Importantly, impairing oligomerization of hIRE1α LD abolished IRE1’s activity in living cells. Our results provide evidence for a unifying mechanism of IRE1 activation that relies on unfolded protein binding-induced oligomerization.

scholarly journals Possible involvement of endoplasmic reticulum stress in the pathogenesis of Alzheimer’s disease

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Toru Hosoi ◽  
Jun Nomura ◽  
Koichiro Ozawa ◽  
Akinori Nishi ◽  
Yasuyuki Nomura
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Quality ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe endoplasmic reticulum (ER) is an organelle that plays a crucial role in protein quality control such as protein folding. Evidence to indicate the involvement of ER in maintaining cellular homeostasis is increasing. However, when cells are exposed to stressful conditions, which perturb ER function, unfolded proteins accumulate leading to ER stress. Cells then activate the unfolded protein response (UPR) to cope with this stressful condition. In the present review, we will discuss and summarize recent advances in research on the basic mechanisms of the UPR. We also discuss the possible involvement of ER stress in the pathogenesis of Alzheimer’s disease (AD). Potential therapeutic opportunities for diseases targeting ER stress is also described.

scholarly journals The Unfolded Protein Response: An Overview

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 384
Author(s):  
Adam Read ◽  
Martin Schröder
Keyword(s):  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Unfolded Protein Response ◽  
Protein Homeostasis ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Altered Glycosylation ◽  
Stressed Cells ◽  
The Unfolded Protein Response ◽  
Protein Response

The unfolded protein response is the mechanism by which cells control endoplasmic reticulum (ER) protein homeostasis. Under normal conditions, the UPR is not activated; however, under certain stresses, such as hypoxia or altered glycosylation, the UPR can be activated due to an accumulation of unfolded proteins. The activation of the UPR involves three signaling pathways, IRE1, PERK and ATF6, which all play vital roles in returning protein homeostasis to levels seen in non-stressed cells. IRE1 is the best studied of the three pathways, as it is the only pathway present in Saccharomyces cerevisiae. This pathway involves spliceosome independent splicing of HAC1 or XBP1 in yeast and mammalians cells, respectively. PERK limits protein synthesis, therefore reducing the number of new proteins requiring folding. ATF6 is translocated and proteolytically cleaved, releasing a NH2 domain fragment which is transported to the nucleus and which affects gene expression. If the UPR is unsuccessful at reducing the load of unfolded proteins in the ER and the UPR signals remain activated, this can lead to programmed cell death.

scholarly journals Endoplasmic reticulum stress as target for treatment of hearing loss

STEMedicine ◽  
2020 ◽  
Vol 1 (3) ◽  
pp. e21
Author(s):  
Yanfei Wang ◽  
Zhigang Xu
Keyword(s):  
Endoplasmic Reticulum ◽  
Hearing Loss ◽  
Er Stress ◽  
Protein Biosynthesis ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Global Protein Synthesis ◽  
Acquired Hearing Loss ◽  
The Unfolded Protein Response ◽  
Protein Response

The endoplasmic reticulum (ER) plays pivotal roles in coordinating protein biosynthesis and processing. Under ER stress, when excessive misfolded or unfolded proteins are accumulated in the ER, the unfolded protein response (UPR) is activated. The UPR blocks global protein synthesis while activates chaperone expression, eventually leading to the alleviation of ER stress. However, prolonged UPR induces cell death. ER stress has been associated with various types of diseases. Recently, increasing evidences suggest that ER stress and UPR are also involved in hearing loss. In the present review, we will discuss the role of ER stress in hereditary hearing loss as well as acquired hearing loss. Moreover, we will discuss the emerging ER stress-based treatment of hearing loss. Further investigations are warranted to understand the mechanisms in detail how ER stress contributes to hearing loss, which will help us develop better ER stress-related treatments.

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