Endoplasmic reticulum stress in biological processing and disease

The ability of translated cellular proteins to perform their functions requires their proper folding after synthesis. The endoplasmic reticulum (ER) is responsible for coordinating protein folding and maturation. Infections, genetic mutations, environmental factors and many other conditions can lead to challenges to the ER known as ER stress. Altering ER homeostasis results in accumulation of misfolded or unfolded proteins. To eliminate this problem, a response is initiated by the cell called the unfolded protein response (UPR), which involves multiple signaling pathways. Prolonged ER stress or a dysregulated UPR can lead to premature apoptosis and an exaggerated inflammatory response. Following these discoveries, ER stress was shown to be related to several chronic diseases, such as diabetes mellitus, neurodegenerative disorders, fatty liver disease and inflammatory bowel disease that have not yet been clearly demonstrated pathophysiologically. Here, we review the field and present up-to-date information on the relationship between biological processing, ER stress, UPR, and several chronic diseases.

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

Frontiers in Physiology ◽

10.3389/fphys.2021.665622 ◽

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.

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Endoplasmic reticulum stress and the development of endothelial dysfunction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00437.2016 ◽

2017 ◽

Vol 312 (3) ◽

pp. H355-H367 ◽

Cited By ~ 34

Author(s):

M. L. Battson ◽

D. M. Lee ◽

C. L. Gentile

Keyword(s):

Endoplasmic Reticulum ◽

Endothelial Dysfunction ◽

Er Stress ◽

Critical Role ◽

Unfolded Protein ◽

Vasoactive Substances ◽

Important Regulator ◽

The Unfolded Protein Response ◽

Protein Response ◽

Er Homeostasis

The vascular endothelium plays a critical role in cardiovascular homeostasis, and thus identifying the underlying causes of endothelial dysfunction has important clinical implications. In this regard, the endoplasmic reticulum (ER) has recently emerged as an important regulator of metabolic processes. Dysfunction within the ER, broadly termed ER stress, evokes the unfolded protein response (UPR), an adaptive pathway that aims to restore ER homeostasis. Although the UPR is the first line of defense against ER stress, chronic activation of the UPR leads to cell dysfunction and death and has recently been implicated in the pathogenesis of endothelial dysfunction. Numerous risk factors for endothelial dysfunction can induce ER stress, which may in turn disrupt endothelial function via direct effects on endothelium-derived vasoactive substances or by activating other pathogenic cellular networks such as inflammation and oxidative stress. This review summarizes the available data linking ER stress to endothelial dysfunction.

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Coordination of stress, Ca2+, and immunogenic signaling pathways by PERK at the endoplasmic reticulum

Biological Chemistry ◽

10.1515/hsz-2016-0108 ◽

2016 ◽

Vol 397 (7) ◽

pp. 649-656 ◽

Cited By ~ 10

Author(s):

Alexander R. van Vliet ◽

Abhishek D. Garg ◽

Patrizia Agostinis

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Signaling Pathways ◽

Unfolded Protein ◽

Independent Functions ◽

Intracellular Ca ◽

Stress Signals ◽

The Unfolded Protein Response ◽

Protein Response ◽

Er Homeostasis

AbstractThe endoplasmic reticulum (ER) is the main coordinator of intracellular Ca2+signaling, protein synthesis, and folding. The ER is also implicated in the formation of contact sites with other organelles and structures, including mitochondria, plasma membrane (PM), and endosomes, thereby orchestrating through interorganelle signaling pathways, a variety of cellular responses including Ca2+homeostasis, metabolism, and cell death signaling. Upon loss of its folding capacity, incited by a number of stress signals including those elicited by various anticancer therapies, the unfolded protein response (UPR) is launched to restore ER homeostasis. The ER stress sensor protein kinase RNA-like ER kinase (PERK) is a key mediator of the UPR and its role during ER stress has been largely recognized. However, growing evidence suggests that PERK may govern signaling pathways through UPR-independent functions. Here, we discuss emerging noncanonical roles of PERK with particular relevance for the induction of danger or immunogenic signaling and interorganelle communication.

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

Endoplasmic Reticulum Stress in Diseases ◽

10.1515/ersc-2015-0008 ◽

2015 ◽

Vol 2 (1) ◽

Cited By ~ 2

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.

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Endoplasmic reticulum stress as target for treatment of hearing loss

STEMedicine ◽

10.37175/stemedicine.v1i3.21 ◽

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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Adaptation to Endoplasmic Reticulum Stress Requires Transphosphorylation within the Activation Loop of Protein Kinases Kin1 and Kin2, Orthologs of Human Microtubule Affinity-Regulating Kinase

Molecular and Cellular Biology ◽

10.1128/mcb.00266-18 ◽

2018 ◽

Vol 38 (23) ◽

Author(s):

Chandrima Ghosh ◽

Leena Sathe ◽

Joel David Paprocki ◽

Valerica Raicu ◽

Madhusudan Dey

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Cellular Membrane ◽

Kinase Domain ◽

Activation Loop ◽

Content Type ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response ◽

Er Homeostasis

ABSTRACT Perturbations in endoplasmic reticulum (ER) homeostasis, a condition termed ER stress, activate the unfolded protein response (UPR), an intracellular network of signaling pathways. Recently, we have shown that protein kinase Kin1 and its paralog, Kin2, in the budding yeast Saccharomyces cerevisiae (orthologs of microtubule affinity-regulating kinase in humans) contribute to the UPR function. These Kin kinases contain a conserved kinase domain and an autoinhibitory kinase-associated 1 (KA1) domain separated by a long undefined domain. Here, we show that Kin1 or Kin2 protein requires minimally a kinase domain and an adjacent kinase extension region (KER) for UPR function. We also show that the functional mini-Kin2 protein is predominantly visualized inside the cells and precipitated with the cellular membrane fraction, suggesting its association with the cellular endomembrane system. Furthermore, we show that transphosphorylation of the Kin1 residue T302 and the analogous Kin2 residue T281 within the activation loop are important for full kinase activity. Collectively, our data suggest that, during ER stress, the Kin kinase domain is released from its autoinhibitory KA1 domain and is activated by transphosphorylation.

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The proteasome biogenesis regulator Rpn4 cooperates with the unfolded protein response to promote resistance to endoplasmic reticulum stress

10.1101/457077 ◽

2018 ◽

Author(s):

Rolf M. Schmidt ◽

Sebastian Schuck

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein Response ◽

Protein Misfolding ◽

Misfolded Proteins ◽

Secretory Proteins ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response ◽

Multiple Signaling

ABSTRACTMisfolded proteins in the endoplasmic reticulum (ER) activate the unfolded protein response (UPR), which enhances protein folding to restore homeostasis. Additional pathways respond to ER stress, but how they help counteract protein misfolding is incompletely understood. Here, we develop a titratable system for the induction of ER stress in yeast to enable a genetic screen for factors that augment stress resistance independently of the UPR. We identify the proteasome biogenesis regulator Rpn4 and show that it cooperates with the UPR. Rpn4 abundance increases during ER stress, first by a post-transcriptional, then by a transcriptional mechanism. Induction of RPN4 transcription is triggered by cytosolic mislocalization of secretory proteins, is mediated by multiple signaling pathways and accelerates clearance of misfolded proteins from the cytosol. Thus, Rpn4 and the UPR are complementary elements of a modular cross-compartment response to ER stress.

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

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/9270107 ◽

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.

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Methods for Monitoring Endoplasmic Reticulum Stress and the Unfolded Protein Response

International Journal of Cell Biology ◽

10.1155/2010/830307 ◽

2010 ◽

Vol 2010 ◽

pp. 1-11 ◽

Cited By ~ 132

Author(s):

Afshin Samali ◽

Una FitzGerald ◽

Shane Deegan ◽

Sanjeev Gupta

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein Response ◽

Model Systems ◽

Unfolded Proteins ◽

Unfolded Protein ◽

Cellular Repair ◽

Standard Set ◽

The Unfolded Protein Response ◽

Protein Response

The endoplasmic reticulum (ER) is the site of folding of membrane and secreted proteins in the cell. Physiological or pathological processes that disturb protein folding in the endoplasmic reticulum cause ER stress and activate a set of signaling pathways termed the Unfolded Protein Response (UPR). The UPR can promote cellular repair and sustained survival by reducing the load of unfolded proteins through upregulation of chaperones and global attenuation of protein synthesis. Research into ER stress and the UPR continues to grow at a rapid rate as many new investigators are entering the field. There are also many researchers not working directly on ER stress, but who wish to determine whether this response is activated in the system they are studying: thus, it is important to list a standard set of criteria for monitoring UPR in different model systems. Here, we discuss approaches that can be used by researchers to plan and interpret experiments aimed at evaluating whether the UPR and related processes are activated. We would like to emphasize that no individual assay is guaranteed to be the most appropriate one in every situation and strongly recommend the use of multiple assays to verify UPR activation.

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

Biological Chemistry ◽

10.1515/hsz-2013-0174 ◽

2014 ◽

Vol 395 (1) ◽

pp. 1-13 ◽

Cited By ~ 107

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.

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