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Endoplasmic Reticulum Stress and Unfolded Protein Response
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Endoplasmic Reticulum Stress and Unfolded Protein Response

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 105588

Special Issue Editors

Prof. Dr. Kazunori Imaizumi

E-Mail Website
Guest Editor
Department of Biochemistry, Institute of Biomedical & Health Sciences, Hiroshima University, Minami‐ku, Hiroshima, Japan
Interests: ER stress; neurodegeneration; cell biology; OASIS family; osteogenesis
Assoc. Prof. Dr. Atsushi Saito

E-Mail Website
Guest Editor
Department of Stress Protein Processing, Institute of Biomedical & Health Sciences, Hiroshima University, Minami‐ku, Hiroshima, Japan
Interests: ER stress; neuroscience; cell differentiation; cell biology

Special Issue Information

Dear Colleagues,

The endoplasmic reticulum (ER) plays a role in the maintenance of numerous aspects of cellular and organismal homeostasis by folding, modifying, and exporting nascent secretory and transmembrane proteins. Failure of the ER's adaptive capacity results in accumulation of unfolded or malfolded proteins in the ER lumen (ER stress). To avoid cellular damage, mammalian cells activate the specific signals from the ER to the cytosol or nucleus to enhance the capacity for protein folding, attenuate the synthesis of proteins, and degrade unfolded proteins. These signaling pathways are collectively known as the unfolded protein response (UPR). UPR was originally described as a system by which cells evade damage in response to acute ER perturbation. However, recent advances have revealed that UPR also regulates cell differentiation and maturation or basal cellular homeostasis. Further, ER stress has been reported to have relationships with neurodegenerative diseases, diabetes, metabolic syndromes, and cancer. Therefore, it has been attracting attention in terms of elucidating pathogenic mechanisms, and developing therapeutics.

This Special Issue provides diverse aspects of ER stress and UPR in various physiological and pathological events. We invite authors to submit original research and review articles related to any research into ER stress and UPR signaling.

Prof. Dr. Kazunori Imaizumi
Assoc. Prof. Dr. Atsushi Saito
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • ER stress
  • UPR signaling
  • Physiological ER stress
  • Protein folding
  • Unfolded proteins
  • ER stress sensors
  • ER-associated degradation
  • Protein quality control
  • ER stress-induced cell death
  • Protein misfolding disease

Related Special Issue

Published Papers (16 papers)

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Research

Jump to: Review

18 pages, 2366 KiB  
Article
Modulating Expression of Thioredoxin Interacting Protein (TXNIP) Prevents Secondary Damage and Preserves Visual Function in a Mouse Model of Ischemia/Reperfusion
by Maha Coucha, Ahmed Y. Shanab, Mohamed Sayed, Almira Vazdarjanova and Azza B. El-Remessy
Int. J. Mol. Sci. 2019, 20(16), 3969; https://doi.org/10.3390/ijms20163969 - 15 Aug 2019
Cited by 12 | Viewed by 3291
Abstract
Retinal neurodegeneration, an early characteristic of several blinding diseases, triggers glial activation, resulting in inflammation, secondary damage and visual impairment. Treatments that aim only at neuroprotection have failed clinically. Here, we examine the impact of modulating thioredoxin interacting protein (TXNIP) to the inflammatory [...] Read more.
Retinal neurodegeneration, an early characteristic of several blinding diseases, triggers glial activation, resulting in inflammation, secondary damage and visual impairment. Treatments that aim only at neuroprotection have failed clinically. Here, we examine the impact of modulating thioredoxin interacting protein (TXNIP) to the inflammatory secondary damage and visual impairment in a model of ischemia/reperfusion (IR). Wild type (WT) and TXNIP knockout (TKO) mice underwent IR injury by increasing intraocular pressure for 40 min, followed by reperfusion. An additional group of WT mice received intravitreal TXNIP-antisense oligomers (ASO, 100 µg/2 µL) 2 days post IR injury. Activation of Müller glial cells, apoptosis and expression of inflammasome markers and visual function were assessed. IR injury triggered early TXNIP mRNA expression that persisted for 14 days and was localized within activated Müller cells in WT-IR, compared to sham controls. Exposure of Müller cells to hypoxia-reoxygenation injury triggered endoplasmic reticulum (ER) stress markers and inflammasome activation in WT cells, but not from TKO cells. Secondary damage was evident by the significant increase in the number of occluded acellular capillaries and visual impairment in IR-WT mice but not in IR-TKO. Intervention with TXNIP-ASO prevented ischemia-induced glial activation and neuro-vascular degeneration, and improved visual function compared to untreated WT. Targeting TXNIP expression may offer an effective approach in the prevention of secondary damage associated with retinal neurodegenerative diseases. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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13 pages, 2466 KiB  
Communication
Pharmacological Targeting of the ER-Resident Chaperones GRP94 or Cyclophilin B Induces Secretion of IL-22 Binding Protein Isoform-1 (IL-22BPi1)
by Paloma Gómez-Fernández, Andoni Urtasun, Ianire Astobiza, Jorge Mena, Iraide Alloza and Koen Vandenbroeck
Int. J. Mol. Sci. 2019, 20(10), 2440; https://doi.org/10.3390/ijms20102440 - 17 May 2019
Cited by 2 | Viewed by 3627
Abstract
Of the three interleukin-22 binding protein (IL-22BP) isoforms produced by the human IL22RA2 gene, IL-22BPi2 and IL-22BPi3 are capable of neutralizing IL-22. The longest isoform, IL-22BPi1, does not bind IL-22, is poorly secreted, and its retention within the endoplasmic reticulum (ER) is associated [...] Read more.
Of the three interleukin-22 binding protein (IL-22BP) isoforms produced by the human IL22RA2 gene, IL-22BPi2 and IL-22BPi3 are capable of neutralizing IL-22. The longest isoform, IL-22BPi1, does not bind IL-22, is poorly secreted, and its retention within the endoplasmic reticulum (ER) is associated with induction of an unfolded protein response (UPR). Therapeutic modulation of IL-22BPi2 and IL-22BPi3 production may be beneficial in IL-22-dependent disorders. Recently, we identified the ER chaperones GRP94 and cyclophilin B in the interactomes of both IL-22BPi1 and IL-22BPi2. In this study, we investigated whether secretion of the IL-22BP isoforms could be modulated by pharmacological targeting of GRP94 and cyclophilin B, either by means of geldanamycin, that binds to the ADP/ATP pocket shared by HSP90 paralogs, or by cyclosporin A, which causes depletion of ER cyclophilin B levels through secretion. We found that geldanamycin and its analogs did not influence secretion of IL-22BPi2 or IL-22BPi3, but significantly enhanced intracellular and secreted levels of IL-22BPi1. The secreted protein was heterogeneously glycosylated, with both high-mannose and complex-type glycoforms present. In addition, cyclosporine A augmented the secretion of IL-22BPi1 and reduced that of IL-22BPi2 and IL-22BPi3. Our data indicate that the ATPase activity of GRP94 and cyclophilin B are instrumental in ER sequestration and degradation of IL-22BPi1, and that blocking these factors mobilizes IL-22BPi1 toward the secretory route. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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15 pages, 3408 KiB  
Article
Endoplasmic Reticulum Stress Impaired Uncoupling Protein 1 Expression via the Suppression of Peroxisome Proliferator-Activated Receptor γ Binding Activity in Mice Beige Adipocytes
by Ana Yuliana, Asumi Daijo, Huei-Fen Jheng, Jungin Kwon, Wataru Nomura, Haruya Takahashi, Takeshi Ara, Teruo Kawada and Tsuyoshi Goto
Int. J. Mol. Sci. 2019, 20(2), 274; https://doi.org/10.3390/ijms20020274 - 11 Jan 2019
Cited by 24 | Viewed by 5082
Abstract
Endoplasmic reticulum (ER) homeostasis is critical in maintaining metabolic regulation. Once it is disrupted due to accumulated unfolded proteins, ER homeostasis is restored via activation of the unfolded protein response (UPR); hence, the UPR affects diverse physiological processes. However, how ER stress influences [...] Read more.
Endoplasmic reticulum (ER) homeostasis is critical in maintaining metabolic regulation. Once it is disrupted due to accumulated unfolded proteins, ER homeostasis is restored via activation of the unfolded protein response (UPR); hence, the UPR affects diverse physiological processes. However, how ER stress influences adipocyte functions is not well known. In this study, we investigated the effect of ER stress in thermogenic capacity of mice beige adipocytes. Here, we show that the expression of uncoupling protein 1 (Ucp1) involved in thermoregulation is severely suppressed under ER stress conditions (afflicted by tunicamycin) in inguinal white adipose tissue (IWAT) both in vitro and in vivo. Further investigation showed that extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were both activated after ER stress stimulation and regulated the mRNA levels of Ucp1 and peroxisome proliferator-activated receptor γ (Pparγ), which is known as a Ucp1 transcriptional activator, in vitro and ex vivo. We also found that Pparγ protein was significantly degraded, reducing its recruitment to the Ucp1 enhancer, thereby downregulating Ucp1 expression. Additionally, only JNK inhibition, but not ERK, rescued the Pparγ protein. These findings provide novel insights into the regulatory effect of ER stress on Ucp1 expression via Pparγ suppression in beige adipocytes. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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Review

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14 pages, 1244 KiB  
Review
Polyamine Catabolism in Acute Kidney Injury
by Kamyar Zahedi, Sharon Barone and Manoocher Soleimani
Int. J. Mol. Sci. 2019, 20(19), 4790; https://doi.org/10.3390/ijms20194790 - 26 Sep 2019
Cited by 22 | Viewed by 3587
Abstract
Acute kidney injury (AKI) refers to an abrupt decrease in kidney function. It affects approximately 7% of all hospitalized patients and almost 35% of intensive care patients. Mortality from acute kidney injury remains high, particularly in critically ill patients, where it can be [...] Read more.
Acute kidney injury (AKI) refers to an abrupt decrease in kidney function. It affects approximately 7% of all hospitalized patients and almost 35% of intensive care patients. Mortality from acute kidney injury remains high, particularly in critically ill patients, where it can be more than 50%. The primary causes of AKI include ischemia/reperfusion (I/R), sepsis, or nephrotoxicity; however, AKI patients may present with a complicated etiology where many of the aforementioned conditions co-exist. Multiple bio-markers associated with renal damage, as well as metabolic and signal transduction pathways that are involved in the mediation of renal dysfunction have been identified as a result of the examination of models, patient samples, and clinical data of AKI of disparate etiologies. These discoveries have enhanced our ability to diagnose AKIs and to begin to elucidate the mechanisms involved in their pathogenesis. Studies in our laboratory revealed that the expression and activity of spermine/spermidine N1-acetyltransferase (SAT1), the rate-limiting enzyme in polyamine back conversion, were enhanced in kidneys of rats after I/R injury. Additional studies revealed that the expression of spermine oxidase (SMOX), another critical enzyme in polyamine catabolism, is also elevated in the kidney and other organs subjected to I/R, septic, toxic, and traumatic injuries. The maladaptive role of polyamine catabolism in the mediation of AKI and other injuries has been clearly demonstrated. This review will examine the biochemical and mechanistic basis of tissue damage brought about by enhanced polyamine degradation and discuss the potential of therapeutic interventions that target polyamine catabolic enzymes or their byproducts for the treatment of AKI. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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17 pages, 1931 KiB  
Review
Impact and Relevance of the Unfolded Protein Response in HNSCC
by Olivier Pluquet and Antoine Galmiche
Int. J. Mol. Sci. 2019, 20(11), 2654; https://doi.org/10.3390/ijms20112654 - 30 May 2019
Cited by 8 | Viewed by 4207
Abstract
Head and neck squamous cell carcinomas (HNSCC) encompass a heterogeneous group of solid tumors that arise from the upper aerodigestive tract. The tumor cells face multiple challenges including an acute demand of protein synthesis often driven by oncogene activation, limited nutrient and oxygen [...] Read more.
Head and neck squamous cell carcinomas (HNSCC) encompass a heterogeneous group of solid tumors that arise from the upper aerodigestive tract. The tumor cells face multiple challenges including an acute demand of protein synthesis often driven by oncogene activation, limited nutrient and oxygen supply and exposure to chemo/radiotherapy, which forces them to develop adaptive mechanisms such as the Unfolded Protein Response (UPR). It is now well documented that the UPR, a homeostatic mechanism, is induced at different stages of cancer progression in response to intrinsic (oncogenic activation) or extrinsic (microenvironment) perturbations. This review will discuss the role of the UPR in HNSCC as well as in the key processes that characterize the physiology of HNSCC. The role of the UPR in the clinical context of HNSCC will also be addressed. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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14 pages, 661 KiB  
Review
The Emerging Role of Electrophiles as a Key Regulator for Endoplasmic Reticulum (ER) Stress
by Nobumasa Takasugi, Hideki Hiraoka, Kengo Nakahara, Shiori Akiyama, Kana Fujikawa, Ryosuke Nomura, Moeka Furuichi and Takashi Uehara
Int. J. Mol. Sci. 2019, 20(7), 1783; https://doi.org/10.3390/ijms20071783 - 10 Apr 2019
Cited by 12 | Viewed by 4231
Abstract
The unfolded protein response (UPR) is activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which is called ER stress. ER stress sensors PERK, IRE1, and ATF6 play a central role in the initiation and regulation of the UPR; they [...] Read more.
The unfolded protein response (UPR) is activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which is called ER stress. ER stress sensors PERK, IRE1, and ATF6 play a central role in the initiation and regulation of the UPR; they inhibit novel protein synthesis and upregulate ER chaperones, such as protein disulfide isomerase, to remove unfolded proteins. However, when recovery from ER stress is difficult, the UPR pathway is activated to eliminate unhealthy cells. This signaling transition is the key event of many human diseases. However, the precise mechanisms are largely unknown. Intriguingly, reactive electrophilic species (RES), which exist in the environment or are produced through cellular metabolism, have been identified as a key player of this transition. In this review, we focused on the function of representative RES: nitric oxide (NO) as a gaseous RES, 4-hydroxynonenal (HNE) as a lipid RES, and methylmercury (MeHg) as an environmental organic compound RES, to outline the relationship between ER stress and RES. Modulation by RES might be a target for the development of next-generation therapy for ER stress-associated diseases. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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21 pages, 1807 KiB  
Review
Endoplasmic Reticulum Stress: A Critical Molecular Driver of Endothelial Dysfunction and Cardiovascular Disturbances Associated with Diabetes
by Hatem Maamoun, Shahenda S. Abdelsalam, Asad Zeidan, Hesham M. Korashy and Abdelali Agouni
Int. J. Mol. Sci. 2019, 20(7), 1658; https://doi.org/10.3390/ijms20071658 - 03 Apr 2019
Cited by 82 | Viewed by 7098
Abstract
Physical inactivity and sedentary lifestyle contribute to the widespread epidemic of obesity among both adults and children leading to rising cases of diabetes. Cardiovascular disease complications associated with obesity and diabetes are closely linked to insulin resistance and its complex implications on vascular [...] Read more.
Physical inactivity and sedentary lifestyle contribute to the widespread epidemic of obesity among both adults and children leading to rising cases of diabetes. Cardiovascular disease complications associated with obesity and diabetes are closely linked to insulin resistance and its complex implications on vascular cells particularly endothelial cells. Endoplasmic reticulum (ER) stress is activated following disruption in post-translational protein folding and maturation within the ER in metabolic conditions characterized by heavy demand on protein synthesis, such as obesity and diabetes. ER stress has gained much interest as a key bridging and converging molecular link between insulin resistance, oxidative stress, and endothelial cell dysfunction and, hence, represents an interesting drug target for diabetes and its cardiovascular complications. We reviewed here the role of ER stress in endothelial cell dysfunction, the primary step in the onset of atherosclerosis and cardiovascular disease. We specifically focused on the contribution of oxidative stress, insulin resistance, endothelial cell death, and cellular inflammation caused by ER stress in endothelial cell dysfunction and the process of atherogenesis. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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24 pages, 700 KiB  
Review
Role of Endoplasmic Reticulum Stress in the Anticancer Activity of Natural Compounds
by Patrizia Limonta, Roberta M. Moretti, Monica Marzagalli, Fabrizio Fontana, Michela Raimondi and Marina Montagnani Marelli
Int. J. Mol. Sci. 2019, 20(4), 961; https://doi.org/10.3390/ijms20040961 - 22 Feb 2019
Cited by 95 | Viewed by 8073
Abstract
Cancer represents a serious global health problem, and its incidence and mortality are rapidly growing worldwide. One of the main causes of the failure of an anticancer treatment is the development of drug resistance by cancer cells. Therefore, it is necessary to develop [...] Read more.
Cancer represents a serious global health problem, and its incidence and mortality are rapidly growing worldwide. One of the main causes of the failure of an anticancer treatment is the development of drug resistance by cancer cells. Therefore, it is necessary to develop new drugs characterized by better pharmacological and toxicological profiles. Natural compounds can represent an optimal collection of bioactive molecules. Many natural compounds have been proven to possess anticancer effects in different types of tumors, but often the molecular mechanisms associated with their cytotoxicity are not completely understood. The endoplasmic reticulum (ER) is an organelle involved in multiple cellular processes. Alteration of ER homeostasis and its appropriate functioning originates a cascade of signaling events known as ER stress response or unfolded protein response (UPR). The UPR pathways involve three different sensors (protein kinase RNA(PKR)-like ER kinase (PERK), inositol requiring enzyme1α (IRE1) and activating transcription factor 6 (ATF6)) residing on the ER membranes. Although the main purpose of UPR is to restore this organelle’s homeostasis, a persistent UPR can trigger cell death pathways such as apoptosis. There is a growing body of evidence showing that ER stress may play a role in the cytotoxicity of many natural compounds. In this review we present an overview of different plant-derived natural compounds, such as curcumin, resveratrol, green tea polyphenols, tocotrienols, and garcinia derivates, that exert their anticancer activity via ER stress modulation in different human cancers. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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17 pages, 1643 KiB  
Review
Endoplasmic Reticulum Stress and Unfolded Protein Response in Breast Cancer: The Balance between Apoptosis and Autophagy and Its Role in Drug Resistance
by Lorenza Sisinni, Michele Pietrafesa, Silvia Lepore, Francesca Maddalena, Valentina Condelli, Franca Esposito and Matteo Landriscina
Int. J. Mol. Sci. 2019, 20(4), 857; https://doi.org/10.3390/ijms20040857 - 16 Feb 2019
Cited by 104 | Viewed by 12238
Abstract
The unfolded protein response (UPR) is a stress response activated by the accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER) and its uncontrolled activation is mechanistically responsible for several human pathologies, including metabolic, neurodegenerative, and inflammatory diseases, [...] Read more.
The unfolded protein response (UPR) is a stress response activated by the accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER) and its uncontrolled activation is mechanistically responsible for several human pathologies, including metabolic, neurodegenerative, and inflammatory diseases, and cancer. Indeed, ER stress and the downstream UPR activation lead to changes in the levels and activities of key regulators of cell survival and autophagy and this is physiologically finalized to restore metabolic homeostasis with the integration of pro-death or/and pro-survival signals. By contrast, the chronic activation of UPR in cancer cells is widely considered a mechanism of tumor progression. In this review, we focus on the relationship between ER stress, apoptosis, and autophagy in human breast cancer and the interplay between the activation of UPR and resistance to anticancer therapies with the aim to disclose novel therapeutic scenarios. The hypothesis that autophagy and UPR may provide novel molecular targets in human malignancies is discussed. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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17 pages, 785 KiB  
Review
Hypoxia Induced ER Stress Response as an Adaptive Mechanism in Cancer
by Sandhya Chipurupalli, Elango Kannan, Vinay Tergaonkar, Richard D’Andrea and Nirmal Robinson
Int. J. Mol. Sci. 2019, 20(3), 749; https://doi.org/10.3390/ijms20030749 - 11 Feb 2019
Cited by 78 | Viewed by 8118
Abstract
It is evident that regions within tumors are deprived of oxygen, which makes the microenvironment hypoxic. Cancer cells experiencing hypoxia undergo metabolic alterations and cytoprotective adaptive mechanisms to survive such stringent conditions. While such mechanisms provide potential therapeutic targets, the mechanisms by which [...] Read more.
It is evident that regions within tumors are deprived of oxygen, which makes the microenvironment hypoxic. Cancer cells experiencing hypoxia undergo metabolic alterations and cytoprotective adaptive mechanisms to survive such stringent conditions. While such mechanisms provide potential therapeutic targets, the mechanisms by which hypoxia regulates adaptive responses—such as ER stress response, unfolded protein response (UPR), anti-oxidative responses, and autophagy—remain elusive. In this review, we summarize the complex interplay between hypoxia and the ER stress signaling pathways that are activated in the hypoxic microenvironment of the tumors. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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15 pages, 919 KiB  
Review
A Novel Insight on Endotyping Heterogeneous Severe Asthma Based on Endoplasmic Reticulum Stress: Beyond the “Type 2/Non-Type 2 Dichotomy”
by Jae Seok Jeong, So Ri Kim, Seong Ho Cho and Yong Chul Lee
Int. J. Mol. Sci. 2019, 20(3), 713; https://doi.org/10.3390/ijms20030713 - 07 Feb 2019
Cited by 17 | Viewed by 5183
Abstract
Severe asthma is an extremely heterogeneous clinical syndrome in which diverse cellular and molecular pathobiologic mechanisms exist, namely endotypes. The current system for endotyping severe asthma is largely based on inflammatory cellular profiles and related pathways, namely the dichotomy of type 2 response [...] Read more.
Severe asthma is an extremely heterogeneous clinical syndrome in which diverse cellular and molecular pathobiologic mechanisms exist, namely endotypes. The current system for endotyping severe asthma is largely based on inflammatory cellular profiles and related pathways, namely the dichotomy of type 2 response (resulting in eosinophilic inflammation) and non-type 2 response (reinforcing non-eosinophilic inflammation involving neutrophils or less inflammatory cells), forming the basis of a development strategy for novel therapies. Although specific subgroups of type 2 severe asthma patients may derive benefit from modern precision medicine targeting type 2 cytokines, there is no approved and effective therapeutic agent for non-type 2 severe asthma, which comprises nearly 50% of all asthma patients. Importantly, the critical implication of endoplasmic reticulum (ER) stress and unfolded protein response—in close relation with several pivotal cellular immune/inflammatory platforms including mitochondria, NLRP3 inflammasome, and phosphoinositide 3-kinase-δ—in the generation of corticosteroid resistance is now being increasingly demonstrated in numerous experimental settings of severe asthma. Consistent with these findings, recent clinical data from a large European severe asthma cohort, in which molecular phenotyping as well as diverse clinical and physiological parameters from severe asthmatic patients were incorporated, suggest a brand new framework for endotyping severe asthma in relation to ER-associated mitochondria and inflammasome pathways. These findings highlight the view that ER stress-associated molecular pathways may serve as a unique endotype of severe asthma, and thus present a novel insight into the current knowledge and future development of treatment to overcome corticosteroid resistance in heterogeneous severe asthma. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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16 pages, 928 KiB  
Review
Naturally Occurring Hepatitis B Virus Mutations Leading to Endoplasmic Reticulum Stress and Their Contribution to the Progression of Hepatocellular Carcinoma
by Yu-Min Choi, So-Young Lee and Bum-Joon Kim
Int. J. Mol. Sci. 2019, 20(3), 597; https://doi.org/10.3390/ijms20030597 - 30 Jan 2019
Cited by 49 | Viewed by 7767
Abstract
Hepatitis B virus (HBV) infection is a global health problem that causes a wide range of pathological outcomes, including cirrhosis and hepatocellular carcinoma (HCC). Endoplasmic reticulum (ER) stress induction by HBV infection has been implicated in liver carcinogenesis and disease progression with chronic [...] Read more.
Hepatitis B virus (HBV) infection is a global health problem that causes a wide range of pathological outcomes, including cirrhosis and hepatocellular carcinoma (HCC). Endoplasmic reticulum (ER) stress induction by HBV infection has been implicated in liver carcinogenesis and disease progression with chronic inflammation via enhanced inflammation, oxidative stress-mediated DNA damage, and hepatocyte proliferation. In the natural course of HBV infection, the accumulation of naturally occurring mutations in the HBV genome can generate several mutant types of HBV-encoded proteins, including three different proteins in the S ORF (SHBs, MHBs, and LHBs) and HBcAg in the C ORF, which could contribute to enhanced ER stress in infected hepatocytes mainly via increased ER accumulation of mutant proteins. However, it seems that there may be distinct capacity and pathway in ER stress-induction and distinct resulting clinical outcomes between HBV variants. In addition, the role of HBxAg mutations in ER stress remains unknown. However, it has been reported that HBxAg itself could exert ER stress in infected cells, resulting in HCC generation in chronic HBV patients. To date, review papers regarding ER stress-mediated HBV mutation have been limited into a specific mutation type: preS2 deletion. So, in this review, we will discuss details about various mutation types in all four regions of the HBV genome (preS1, preS2, S, and C) related to ER stress and their distinct ER stress mechanisms and clinical outcomes in terms of mutation types. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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19 pages, 1359 KiB  
Review
Endoplasmic Reticulum (ER) Stress and Unfolded Protein Response (UPR) in Mammalian Oocyte Maturation and Preimplantation Embryo Development
by Tao Lin, Jae Eun Lee, Jung Won Kang, Hyeon Yeong Shin, Ju Bin Lee and Dong Il Jin
Int. J. Mol. Sci. 2019, 20(2), 409; https://doi.org/10.3390/ijms20020409 - 18 Jan 2019
Cited by 88 | Viewed by 11864
Abstract
Mammalian oocytes and early embryos derived from in vitro production are highly susceptible to a variety of cellular stresses. During oocyte maturation and preimplantation embryo development, functional proteins must be folded properly in the endoplasmic reticulum (ER) to maintain oocyte and embryo development. [...] Read more.
Mammalian oocytes and early embryos derived from in vitro production are highly susceptible to a variety of cellular stresses. During oocyte maturation and preimplantation embryo development, functional proteins must be folded properly in the endoplasmic reticulum (ER) to maintain oocyte and embryo development. However, some adverse factors negatively impact ER functions and protein synthesis, resulting in the activation of ER stress and unfolded protein response (UPR) signaling pathways. ER stress and UPR signaling have been identified in mammalian oocytes and embryos produced in vitro, suggesting that modulation of ER stress and UPR signaling play very important roles in oocyte maturation and the development of preimplantation embryos. In this review, we briefly describe the current state of knowledge regarding ER stress, UPR signaling pathways, and their roles and mechanisms in mammalian (excluding human) oocyte maturation and preimplantation embryo development. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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13 pages, 917 KiB  
Review
Linking Endoplasmic Reticular Stress and Alternative Splicing
by Nolan T. Carew, Ashley M. Nelson, Zhitao Liang, Sage M. Smith and Christine Milcarek
Int. J. Mol. Sci. 2018, 19(12), 3919; https://doi.org/10.3390/ijms19123919 - 07 Dec 2018
Cited by 9 | Viewed by 4938
Abstract
RNA splicing patterns in antibody-secreting cells are shaped by endoplasmic reticulum stress, ELL2 (eleven-nineteen lysine-rich leukemia gene 2) induction, and changes in the levels of snRNAs. Endoplasmic reticulum stress induces the unfolded protein response comprising a highly conserved set of genes crucial [...] Read more.
RNA splicing patterns in antibody-secreting cells are shaped by endoplasmic reticulum stress, ELL2 (eleven-nineteen lysine-rich leukemia gene 2) induction, and changes in the levels of snRNAs. Endoplasmic reticulum stress induces the unfolded protein response comprising a highly conserved set of genes crucial for cell survival; among these is Ire1, whose auto-phosphorylation drives it to acquire a regulated mRNA decay activity. The mRNA-modifying function of phosphorylated Ire1 non-canonically splices Xbp1 mRNA and yet degrades other cellular mRNAs with related motifs. Naïve splenic B cells will activate Ire1 phosphorylation early on after lipopolysaccharide (LPS) stimulation, within 18 h; large-scale changes in mRNA content and splicing patterns result. Inhibition of the mRNA-degradation function of Ire1 is correlated with further differences in the splicing patterns and a reduction in the mRNA factors for snRNA transcription. Some of the >4000 splicing changes seen at 18 h after LPS stimulation persist into the late stages of antibody secretion, up to 72 h. Meanwhile some early splicing changes are supplanted by new splicing changes introduced by the up-regulation of ELL2, a transcription elongation factor. ELL2 is necessary for immunoglobulin secretion and does this by changing mRNA processing patterns of immunoglobulin heavy chain and >5000 other genes. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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17 pages, 1001 KiB  
Review
Unfolded Protein Response-Dependent Communication and Contact among Endoplasmic Reticulum, Mitochondria, and Plasma Membrane
by Atsushi Saito and Kazunori Imaizumi
Int. J. Mol. Sci. 2018, 19(10), 3215; https://doi.org/10.3390/ijms19103215 - 18 Oct 2018
Cited by 41 | Viewed by 8084
Abstract
The function of the endoplasmic reticulum (ER) can be impaired by changes to the extra- and intracellular environment, such as disruption of calcium homeostasis, expression of mutated proteins, and oxidative stress. In response to disruptions to ER homeostasis, eukaryotic cells activate canonical branches [...] Read more.
The function of the endoplasmic reticulum (ER) can be impaired by changes to the extra- and intracellular environment, such as disruption of calcium homeostasis, expression of mutated proteins, and oxidative stress. In response to disruptions to ER homeostasis, eukaryotic cells activate canonical branches of signal transduction cascades, collectively termed the unfolded protein response (UPR). The UPR functions to remove or recover the activity of misfolded proteins that accumulated in the ER and to avoid irreversible cellular damage. Additionally, the UPR plays unique physiological roles in the regulation of diverse cellular events, including cell differentiation and development and lipid biosynthesis. Recent studies have shown that these important cellular events are also regulated by contact and communication among organelles. These reports suggest strong involvement among the UPR, organelle communication, and regulation of cellular homeostasis. However, the precise mechanisms for the formation of contact sites and the regulation of ER dynamics by the UPR remain unresolved. In this review, we summarize the current understanding of how the UPR regulates morphological changes to the ER and the formation of contact sites between the ER and other organelles. We also review how UPR-dependent connections between the ER and other organelles affect cellular and physiological functions. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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27 pages, 2152 KiB  
Review
Protein Quality Control in the Endoplasmic Reticulum and Cancer
by Hye Won Moon, Hye Gyeong Han and Young Joo Jeon
Int. J. Mol. Sci. 2018, 19(10), 3020; https://doi.org/10.3390/ijms19103020 - 03 Oct 2018
Cited by 55 | Viewed by 7174
Abstract
The endoplasmic reticulum (ER) is an essential compartment of the biosynthesis, folding, assembly, and trafficking of secretory and transmembrane proteins, and consequently, eukaryotic cells possess specialized machineries to ensure that the ER enables the proteins to acquire adequate folding and maturation for maintaining [...] Read more.
The endoplasmic reticulum (ER) is an essential compartment of the biosynthesis, folding, assembly, and trafficking of secretory and transmembrane proteins, and consequently, eukaryotic cells possess specialized machineries to ensure that the ER enables the proteins to acquire adequate folding and maturation for maintaining protein homeostasis, a process which is termed proteostasis. However, a large variety of physiological and pathological perturbations lead to the accumulation of misfolded proteins in the ER, which is referred to as ER stress. To resolve ER stress and restore proteostasis, cells have evolutionary conserved protein quality-control machineries of the ER, consisting of the unfolded protein response (UPR) of the ER, ER-associated degradation (ERAD), and autophagy. Furthermore, protein quality-control machineries of the ER play pivotal roles in the control of differentiation, progression of cell cycle, inflammation, immunity, and aging. Therefore, severe and non-resolvable ER stress is closely associated with tumor development, aggressiveness, and response to therapies for cancer. In this review, we highlight current knowledge in the molecular understanding and physiological relevance of protein quality control of the ER and discuss new insights into how protein quality control of the ER is implicated in the pathogenesis of cancer, which could contribute to therapeutic intervention in cancer. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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