scholarly journals ER homeostasis and autophagy

2017 ◽  
Vol 61 (6) ◽  
pp. 625-635 ◽  
Author(s):  
Matthew Smith ◽  
Simon Wilkinson
Keyword(s):  
Secretory Proteins ◽  
Unfolded Protein ◽  
Effector Pathway ◽  
Autophagy Pathway ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response ◽  
Er Homeostasis ◽  
Effector Mechanisms

The endoplasmic reticulum (ER) is a key site for lipid biosynthesis and folding of nascent transmembrane and secretory proteins. These processes are maintained by careful homeostatic control of the environment within the ER lumen. Signalling sensors within the ER detect perturbations within the lumen (ER stress) and employ downstream signalling cascades that engage effector mechanisms to restore homeostasis. The most studied signalling mechanism that the ER employs is the unfolded protein response (UPR), which is known to increase a number of effector mechanisms, including autophagy. In this chapter, we will discuss the emerging role of autophagy as a UPR effector pathway. We will focus on the recently discovered selective autophagy pathway for ER, ER-phagy, with particular emphasis on the structure and function of known mammalian ER-phagy receptors, namely FAM134B, SEC62, RTN3 and CCPG1. Finally, we conclude with our view of where the future of this field can lead our understanding of the involvement of ER-phagy in ER homeostasis.

scholarly journals The Impact of Endoplasmic Reticulum-Associated Protein Modifications, Folding and Degradation on Lung Structure and Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Emily M. Nakada ◽  
Rui Sun ◽  
Utako Fujii ◽  
James G. Martin
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein ◽  
Lung Structure ◽  
Selective Translation ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response ◽  
Er Homeostasis ◽  
The Impact

The accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) causes ER stress and induces the unfolded protein response (UPR) and other mechanisms to restore ER homeostasis, including translational shutdown, increased targeting of mRNAs for degradation by the IRE1-dependent decay pathway, selective translation of proteins that contribute to the protein folding capacity of the ER, and activation of the ER-associated degradation machinery. When ER stress is excessive or prolonged and these mechanisms fail to restore proteostasis, the UPR triggers the cell to undergo apoptosis. This review also examines the overlooked role of post-translational modifications and their roles in protein processing and effects on ER stress and the UPR. Finally, these effects are examined in the context of lung structure, function, and disease.

Role of unfolded protein response in genital malformation/damage of male mice induced by flutamide

2020 ◽  
Vol 39 (12) ◽  
pp. 1690-1699
Author(s):  
H Yu ◽  
K Wen ◽  
X Zhou ◽  
Y Zhang ◽  
Z Yan ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Messenger Rna ◽  
Hypoxia Inducible Factor ◽  
Reproductive Organs ◽  
Pregnant Mouse ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response

The unfolded protein response (UPR) is one of a switch of autophagy and apoptosis, and the endoplasmic reticulum stress (ERS) which inducing UPR plays a role in the malformations caused by some genetic and environmental factors. Exposure to flutamide during pregnancy will also cause abnormalities in some male offspring reproductive organs such as cryptorchidism. In this study, after administered the pregnant mouse orally at a dose of 300 mg/kg body weight every day during gestational day (GD)12 to GD18, flutamide can not only caused hypospadias in the male mouse offspring but also damaged the morphology and function of their testis. And the expression of UPR-related genes and proteins, autophagy, apoptosis, and angiogenesis-related genes of the damaged/teratogenic testis and penis in the mice were investigated to determine the role of UPR in this model. It was found that flutamide activated maybe the Atg7-Atg3-Lc3 pathway through the UPR pathway, caused cells excessive autophagy and apoptosis, and inhibited the formation of penile and testicular blood vessels by activating UPR and affecting the messenger RNA level of vascular endothelial growth factor and hypoxia-inducible factor 1.

scholarly journals Cysteine cross-linking in native membranes establishes the transmembrane architecture of Ire1

2021 ◽  
Vol 220 (8) ◽  
Author(s):  
Kristina Väth ◽  
Carsten Mattes ◽  
John Reinhard ◽  
Roberto Covino ◽  
Heike Stumpf ◽  
...  
Keyword(s):  
Lipid Bilayer ◽  
Cross Linking ◽  
Secretory Proteins ◽  
Transmembrane Helices ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis ◽  
Protein Load

The ER is a key organelle of membrane biogenesis and crucial for the folding of both membrane and secretory proteins. Sensors of the unfolded protein response (UPR) monitor the unfolded protein load in the ER and convey effector functions for maintaining ER homeostasis. Aberrant compositions of the ER membrane, referred to as lipid bilayer stress, are equally potent activators of the UPR. How the distinct signals from lipid bilayer stress and unfolded proteins are processed by the conserved UPR transducer Ire1 remains unknown. Here, we have generated a functional, cysteine-less variant of Ire1 and performed systematic cysteine cross-linking experiments in native membranes to establish its transmembrane architecture in signaling-active clusters. We show that the transmembrane helices of two neighboring Ire1 molecules adopt an X-shaped configuration independent of the primary cause for ER stress. This suggests that different forms of stress converge in a common, signaling-active transmembrane architecture of Ire1.

scholarly journals The unfolded protein response is required for dendrite morphogenesis

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Xing Wei ◽  
Audrey S Howell ◽  
Xintong Dong ◽  
Caitlin A Taylor ◽  
Roshni C Cooper ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Dendritic Arbors ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Dendritic Branches ◽  
Dendritic Fields ◽  
Protein Response ◽  
Dendrite Morphogenesis ◽  
Er Homeostasis

Precise patterning of dendritic fields is essential for the formation and function of neuronal circuits. During development, dendrites acquire their morphology by exuberant branching. How neurons cope with the increased load of protein production required for this rapid growth is poorly understood. Here we show that the physiological unfolded protein response (UPR) is induced in the highly branched Caenorhabditis elegans sensory neuron PVD during dendrite morphogenesis. Perturbation of the IRE1 arm of the UPR pathway causes loss of dendritic branches, a phenotype that can be rescued by overexpression of the ER chaperone HSP-4 (a homolog of mammalian BiP/ grp78). Surprisingly, a single transmembrane leucine-rich repeat protein, DMA-1, plays a major role in the induction of the UPR and the dendritic phenotype in the UPR mutants. These findings reveal a significant role for the physiological UPR in the maintenance of ER homeostasis during morphogenesis of large dendritic arbors.

scholarly journals Systematic cysteine-crosslinking in native membranes establishes the transmembrane architecture in Ire1 clusters

2019 ◽  
Author(s):  
Kristina Väth ◽  
Roberto Covino ◽  
John Reinhard ◽  
Gerhard Hummer ◽  
Robert Ernst
Keyword(s):  
Lipid Bilayer ◽  
Secretory Proteins ◽  
Transmembrane Helices ◽  
Unfolded Protein ◽  
Proteotoxic Stress ◽  
Stress Sensors ◽  
Obesity And Diabetes ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

AbstractThe endoplasmic reticulum (ER) is a key organelle of membrane biogenesis and crucial for the folding of both membrane and secretory proteins. Stress sensors of the unfolded protein response (UPR) monitor the unfolded protein load in the ER and convey effector functions for the maintenance of ER homeostasis. More recently, it became clear that aberrant compositions of the ER membrane, referred to as lipid bilayer stress, are equally potent activators of the UPR with important implications in obesity and diabetes. How the distinct signals from lipid bilayer stress and proteotoxic stress are processed by the highly conserved UPR transducer Ire1 remains unknown. Here, we have generated a functional, cysteine-less variant of Ire1 and performed systematic cysteine crosslinking experiments to establish the transmembrane architecture of signaling-active clusters in native membranes. We show that the transmembrane helices of two neighboring Ire1 molecules adopt an X-shaped configuration and that this configuration is independent of the primary cause for ER stress. Based on these findings, we propose that different forms of stress converge in a single, signaling-active conformation of Ire1.

scholarly journals Role of Endoplasmic Reticulum Stress in Atherosclerosis and Its Potential as a Therapeutic Target

2020 ◽  
Vol 2020 ◽  
pp. 1-15
Author(s):  
Shengjie Yang ◽  
Min Wu ◽  
Xiaoya Li ◽  
Ran Zhao ◽  
Yixi Zhao ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein ◽  
Atherosclerotic Lesions ◽  
Different Types ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis ◽  
Progression Of Atherosclerosis

Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis and related cardiovascular diseases (CVDs). It occurs due to various pathological factors that interfere with ER homeostasis, resulting in the accumulation of unfolded or misfolded proteins in the ER lumen, thereby causing ER dysfunction. Here, we discuss the role of ER stress in different types of cells in atherosclerotic lesions. This discussion includes the activation of apoptotic and inflammatory pathways induced by prolonged ER stress, especially in advanced lesional macrophages and endothelial cells (ECs), as well as common atherosclerosis-related ER stressors in different lesional cells, which all contribute to the clinical progression of atherosclerosis. In view of the important role of ER stress and the unfolded protein response (UPR) signaling pathways in atherosclerosis and CVDs, targeting these processes to reduce ER stress may be a novel therapeutic strategy.

Stressed to death – mechanisms of ER stress-induced cell death

2014 ◽  
Vol 395 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Natalia Sovolyova ◽  
Sandra Healy ◽  
Afshin Samali ◽  
Susan E. Logue
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Post Translational Modification ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Cell Death Pathway ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response ◽  
Er Homeostasis

Abstract The endoplasmic reticulum (ER) is a highly dynamic organelle of fundamental importance present in all eukaryotic cells. The majority of synthesized structural and secreted proteins undergo post-translational modification, folding and oligomerization in the ER lumen, enabling proteins to carry out their physiological functions. Therefore, maintenance of ER homeostasis and function is imperative for proper cellular function. Physiological and pathological conditions can disturb ER homeostasis and thus negatively impact upon protein folding, resulting in an accumulation of unfolded proteins. Examples include hypoxia, hypo- and hyperglycemia, acidosis, and fluxes in calcium levels. Increased levels of unfolded/misfolded proteins within the ER lumen triggers a condition commonly referred to as ‘ER stress’. To combat ER stress, cells have evolved a highly conserved adaptive stress response referred to as the unfolded protein response (UPR). UPR signaling affords the cell a ‘window of opportunity’ for stress resolution however, if prolonged or excessive the UPR is insufficient and ER stress-induced cell death ensues. This review discusses the role of ER stress sensors IRE1, PERK and ATF6, describing their role in ER stress-induced death signaling with specific emphasis placed upon the importance of the intrinsic cell death pathway and Bcl-2 family regulation.

PERK in the life and death of the pancreatic β-cell

2007 ◽  
Vol 35 (5) ◽  
pp. 1205-1207 ◽  
Author(s):  
T.P. Herbert
Keyword(s):  
Short Review ◽  
Β Cell ◽  
Cellular Survival ◽  
Life And Death ◽  
Unfolded Protein ◽  
Dependent Protein ◽  
The Unfolded Protein Response ◽  
And Function ◽  
Protein Response

To ensure cellular survival to ER (endoplasmic reticulum) stress, PERK [PKR (double-stranded-RNA-dependent protein kinase)-like ER kinase], an ER transmembrane kinase, is activated as part of the unfolded protein response. PERK is highly expressed in pancreatic β-cells and is essential in the β-cell's development, differentiation and function. However, chronic activation of PERK can induce cell death, and its activation has been implicated in both Type 1 and Type 2 diabetes. This short review aims to provide an insight into our current understanding of the role of PERK in the life and death of the β-cell.

scholarly journals Advanced genomics identifies growth effectors for proteotoxic ER stress recovery in Arabidopsis thaliana

2022 ◽  
Vol 5 (1) ◽  
Author(s):  
Dae Kwan Ko ◽  
Federica Brandizzi
Keyword(s):  
Arabidopsis Thaliana ◽  
Er Stress ◽  
Functional Roles ◽  
Unfolded Protein ◽  
Underlying Mechanisms ◽  
Set Up ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

AbstractAdverse environmental and pathophysiological situations can overwhelm the biosynthetic capacity of the endoplasmic reticulum (ER), igniting a potentially lethal condition known as ER stress. ER stress hampers growth and triggers a conserved cytoprotective signaling cascade, the unfolded protein response (UPR) for ER homeostasis. As ER stress subsides, growth is resumed. Despite the pivotal role of the UPR in growth restoration, the underlying mechanisms for growth resumption are yet unknown. To discover these, we undertook a genomics approach in the model plant species Arabidopsis thaliana and mined the gene reprogramming roles of the UPR modulators, basic leucine zipper28 (bZIP28) and bZIP60, in ER stress resolution. Through a network modeling and experimental validation, we identified key genes downstream of the UPR bZIP-transcription factors (bZIP-TFs), and demonstrated their functional roles. Our analyses have set up a critical pipeline for functional gene discovery in ER stress resolution with broad applicability across multicellular eukaryotes.

scholarly journals Confounding Roles of ER Stress and the Unfolded Protein Response in Skeletal Muscle Atrophy

2021 ◽  
Vol 22 (5) ◽  
pp. 2567
Author(s):  
Yann S. Gallot ◽  
Kyle R. Bohnert
Keyword(s):  
Skeletal Muscle ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Smooth Endoplasmic Reticulum ◽  
Skeletal Muscle Atrophy ◽  
Unfolded Protein ◽  
The Individual ◽  
The Unfolded Protein Response ◽  
Protein Response

Skeletal muscle is an essential organ, responsible for many physiological functions such as breathing, locomotion, postural maintenance, thermoregulation, and metabolism. Interestingly, skeletal muscle is a highly plastic tissue, capable of adapting to anabolic and catabolic stimuli. Skeletal muscle contains a specialized smooth endoplasmic reticulum (ER), known as the sarcoplasmic reticulum, composed of an extensive network of tubules. In addition to the role of folding and trafficking proteins within the cell, this specialized organelle is responsible for the regulated release of calcium ions (Ca2+) into the cytoplasm to trigger a muscle contraction. Under various stimuli, such as exercise, hypoxia, imbalances in calcium levels, ER homeostasis is disturbed and the amount of misfolded and/or unfolded proteins accumulates in the ER. This accumulation of misfolded/unfolded protein causes ER stress and leads to the activation of the unfolded protein response (UPR). Interestingly, the role of the UPR in skeletal muscle has only just begun to be elucidated. Accumulating evidence suggests that ER stress and UPR markers are drastically induced in various catabolic stimuli including cachexia, denervation, nutrient deprivation, aging, and disease. Evidence indicates some of these molecules appear to be aiding the skeletal muscle in regaining homeostasis whereas others demonstrate the ability to drive the atrophy. Continued investigations into the individual molecules of this complex pathway are necessary to fully understand the mechanisms.

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