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Study of Endoplasmic Reticulum Stress and Unfolded Protein Response

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (10 August 2023) | Viewed by 15632

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Special Issue Editor

Prof. Dr. Boaz Tirosh

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Guest Editor

1. Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem 9112002, Israel
2. The Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA
Interests: unfolded protein response; cancer

Special Issue Information

Dear Colleagues,

Adaptation to stress is critical to maintain homeostasis. However, when stress responses become chronic, a new homeostasis is reached, usually associated with pathology. In this regard, the unfolded protein response (UPR), a signaling pathway required for adaptation to perturbations in protein folding in the endoplasmic reticulum (ER), is no exception. Chronic UPR promotes various diseases, including diabetes, non-alcoholic steatohepatitis and inflammatory conditions. In cancer, the UPR is involved in tumor progression, metastasis and response to therapy. The field of UPR research is growing rapidly and the recent development of specific and high-affinity pharmacological inhibitors provides novel therapeutic opportunities. This open access Special Issue will bring together original research and review articles on the roles of UPR in pathology, highlighting new mechanisms, approaches, and therapeutic applications for cancer, inflammation and metabolic disorders related to stress adaptation signaling. The main aim of this Special Issue is to provide a platform for the open-source sharing of significant works in the field of UPR, in order to advance our translational understanding for human therapy.

Topics relevant to this Special Issue include, but are not limited to:

Molecular details of UPR activation and return to homeostasis;
Mechanisms of ER stress-mediated cell death;
Roles of the UPR in cell differentiation;
The use of UPR inhibitors for therapy;
The role of UPR in the cancer parenchyma and in the microenvironment;
The role of UPR in immune modulation.

Prof. Dr. Boaz Tirosh
Guest Editor

Manuscript Submission Information

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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
oxidative stress
protein folding
innate immunity
PERK
IRE1
ISR
translation regulation

Published Papers (7 papers)

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16 pages, 4487 KiB

Open AccessArticle

ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway

by Chang-Hoon Lim, Xue-Quan Fang, Hyeji Kang, Taerim Oh, Seonghoon Lee, Young-Seon Kim and Ji-Hong Lim

Int. J. Mol. Sci. 2024, 25(5), 2768; https://doi.org/10.3390/ijms25052768 - 27 Feb 2024

Viewed by 1190

Abstract

Ubiquitin-specific protease 7 inhibitors (USP7i) are considered a novel class of anticancer drugs. Cancer cells occasionally become insensitive to anticancer drugs, known as chemoresistance, by acquiring multidrug resistance, resulting in poor clinical outcomes in patients with cancer. However, the chemoresistance of cancer cells to USP7i (P22077 and P5091) and mechanisms to overcome it have not yet been investigated. In the present study, we generated human cancer cells with acquired resistance to USP7i-induced cell death. Gene expression profiling showed that heat stress response (HSR)- and unfolded protein response (UPR)-related genes were largely upregulated in USP7i-resistant cancer cells. Biochemical studies showed that USP7i induced the phosphorylation and activation of heat shock transcription factor 1 (HSF1), mediated by the endoplasmic reticulum (ER) stress protein kinase R-like ER kinase (PERK) signaling pathway. Inhibition of HSF1 and PERK significantly sensitized cancer cells to USP7i-induced cytotoxicity. Our study demonstrated that the ER stress–PERK axis is responsible for chemoresistance to USP7i, and inhibiting PERK is a potential strategy for improving the anticancer efficacy of USP7i. Full article

(This article belongs to the Special Issue Study of Endoplasmic Reticulum Stress and Unfolded Protein Response)

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11 pages, 2266 KiB

Open AccessArticle

Chemical Chaperone 4-PBA Mitigates Tumor Necrosis Factor Alpha-Induced Endoplasmic Reticulum Stress in Human Airway Smooth Muscle

by Philippe Delmotte, Jane Q. Yap, Debanjali Dasgupta and Gary C. Sieck

Int. J. Mol. Sci. 2023, 24(21), 15816; https://doi.org/10.3390/ijms242115816 - 31 Oct 2023

Cited by 3 | Viewed by 1488

Abstract

Airway inflammation and pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα) underlie the pathophysiology of respiratory diseases, including asthma. Previously, we showed that TNFα activates the inositol-requiring enzyme 1α (IRE1α)/X-box binding protein 1 spliced (XBP1s) endoplasmic reticulum (ER) stress pathway in human airway smooth muscle (hASM) cells. The ER stress pathway is activated by the accumulation of unfolded proteins in the ER. Accordingly, chemical chaperones such as 4-phenylbutyric acid (4-PBA) may reduce ER stress activation. In the present study, we hypothesized that chemical chaperone 4-PBA mitigates TNFα-induced ER stress in hASM cells. hASM cells were isolated from bronchiolar tissue obtained from five patients with no history of smoking or respiratory diseases. The hASM cells’ phenotype was confirmed via the expression of alpha-smooth muscle actin and elongated morphology. hASM cells from the same patient sample were then separated into three 12 h treatment groups: (1) TNFα (20 ng/mL), (2) TNFα + 4-PBA (1 μM, 30 min pretreatment), and (3) untreated control. The expressions of total IRE1α and phosphorylated IRE1α (pIRE1α^S724) were determined through Western blotting. The splicing of XBP1 mRNA was analyzed using RT-PCR. We found that TNFα induced an increase in pIRE1α^S724 phosphorylation, which was mitigated by treatment with chemical chaperone 4-PBA. We also found that TNFα induced an increase in XBP1s mRNA, which was also mitigated by treatment with chemical chaperone 4-PBA. These results support our hypothesis and indicate that chemical chaperone 4-PBA treatment mitigates TNFα-induced ER stress in hASM cells. Full article

(This article belongs to the Special Issue Study of Endoplasmic Reticulum Stress and Unfolded Protein Response)

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21 pages, 8704 KiB

Open AccessArticle

Liraglutide Counteracts Endoplasmic Reticulum Stress in Palmitate-Treated Hypothalamic Neurons without Restoring Mitochondrial Homeostasis

by Haven Griffin, Sarah C. Sullivan, Steven W. Barger, Kevin D. Phelan and Giulia Baldini

Int. J. Mol. Sci. 2023, 24(1), 629; https://doi.org/10.3390/ijms24010629 - 30 Dec 2022

Cited by 1 | Viewed by 1850

Abstract

One feature of high-fat diet-induced neurodegeneration in the hypothalamus is an increased level of palmitate, which is associated with endoplasmic reticulum (ER) stress, loss of CoxIV, mitochondrial fragmentation, and decreased abundance of MC4R. To determine whether antidiabetic drugs protect against ER and/or mitochondrial dysfunction by lipid stress, hypothalamic neurons derived from pre-adult mice and neuronal Neuro2A cells were exposed to elevated palmitate. In the hypothalamic neurons, palmitate exposure increased expression of ER resident proteins, including that of SERCA2, indicating ER stress. Liraglutide reverted such altered ER proteostasis, while metformin only normalized SERCA2 expression. In Neuro2A cells liraglutide, but not metformin, also blunted dilation of the ER induced by palmitate treatment, and enhanced abundance and expression of MC4R at the cell surface. Thus, liraglutide counteracts, more effectively than metformin, altered ER proteostasis, morphology, and folding capacity in neurons exposed to fat. In palmitate-treated hypothalamic neurons, mitochondrial fragmentation took place together with loss of CoxIV and decreased mitochondrial membrane potential (MMP). Metformin, but not liraglutide, reverted mitochondrial fragmentation, and both liraglutide and metformin did not protect against either loss of CoxIV abundance or MMP. Thus, ER recovery from lipid stress can take place in hypothalamic neurons in the absence of recovered mitochondrial homeostasis. Full article

(This article belongs to the Special Issue Study of Endoplasmic Reticulum Stress and Unfolded Protein Response)

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21 pages, 4274 KiB

Open AccessArticle

Endoplasmic Reticulum Homeostasis Regulates TLR4 Expression and Signaling in Mast Cells

by Shatha Boukeileh, Odai Darawshi, Miriam Shmuel, Mohamed Mahameed, Thomas Wilhelm, Priya Dipta, Francesca Forno, Bellam Praveen, Michael Huber, Francesca Levi-Schaffer and Boaz Tirosh

Int. J. Mol. Sci. 2022, 23(19), 11826; https://doi.org/10.3390/ijms231911826 - 5 Oct 2022

Cited by 4 | Viewed by 1854

Abstract

The endoplasmic reticulum (ER) is a dynamic organelle that responds to demand in secretory proteins by undergoing expansion. The mechanisms that control the homeostasis of ER size and function involve the activation of the unfolded protein response (UPR). The UPR plays a role in various effector functions of immune cells. Mast cells (MCs) are highly granular tissue-resident cells and key drivers of allergic inflammation. Their diverse secretory functions in response to activation through the high-affinity receptor for IgE (FcεRI) suggest a role for the UPR in their function. Using human cord blood-derived MCs, we found that FcεRI triggering elevated the expression level and induced activation of the UPR transducers IRE1α and PERK, accompanied by expansion of the ER. In mouse bone marrow-derived MCs and peritoneal MCs, the ER underwent a more moderate expansion, and the UPR was not induced following MC activation. The deletion of IRE1α in mouse MCs did not affect proliferation, survival, degranulation, or cytokine stimulation following FcεRI triggering, but it did diminish the surface expression of TLR4 and the consequent response to LPS. A similar phenotype was observed in human MCs using an IRE1α inhibitor. Our data indicate that the ER of MCs, primarily of humans, undergoes a rapid remodeling in response to activation that promotes responses to TLR4. We suggest that IRE1α inhibition can be a strategy for inhibiting the hyperactivation of MCs by LPS over the course of allergic responses. Full article

(This article belongs to the Special Issue Study of Endoplasmic Reticulum Stress and Unfolded Protein Response)

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19 pages, 4248 KiB

Open AccessArticle

Hepatocyte-Derived Prostaglandin E2-Modulated Macrophage M1-Type Polarization via mTOR-NPC1 Axis-Regulated Cholesterol Transport from Lysosomes to the Endoplasmic Reticulum in Hepatitis B Virus x Protein-Related Nonalcoholic Steatohepatitis

by You Lan, Bo Qian, Hai-Yan Huang, Pan Wang, Ting Li, Qi Yuan, Han-Yu Zhang, Yu-Chun Lin and Zhong-Ning Lin

Int. J. Mol. Sci. 2022, 23(19), 11660; https://doi.org/10.3390/ijms231911660 - 1 Oct 2022

Cited by 8 | Viewed by 3085

Abstract

Lipid metabolic dysregulation and liver inflammation have been reported to be associated with nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain unclear. Hepatitis B virus x protein (HBx) is a risk factor for NASH. Based on metabolomic and transcriptomic screens and public database analysis, we found that HBx-expressing hepatocyte-derived prostaglandin E2 (PGE2) induced macrophage polarization imbalance via prostaglandin E2 receptor 4 (EP4) through in vitro, ex vivo, and in vivo models. Here, we revealed that the M1-type polarization of macrophages induced by endoplasmic reticulum oxidoreductase-1-like protein α (ERO1α)-dependent endoplasmic reticulum stress was associated with the HBx-related hepatic NASH phenotype. Mechanistically, HBx promoted Niemann–Pick type C1 (NPC1)/oxysterol-binding protein-related protein 5 (ORP5)-mediated cholesterol transport from the lysosome to the endoplasmic reticulum via mammalian target of rapamycin (mTOR) activation. This study provides a novel basis for screening potential biomarkers in the macrophage mTOR–cholesterol homeostasis–polarization regulatory signaling pathway and evaluating targeted interventions for HBx-associated NASH. Full article

(This article belongs to the Special Issue Study of Endoplasmic Reticulum Stress and Unfolded Protein Response)

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19 pages, 5231 KiB

Open AccessArticle

The Unfolded Protein Response Sensor PERK Mediates Stiffness-Dependent Adaptation in Glioblastoma Cells

by Mohammad Khoonkari, Dong Liang, Marina Trombetta Lima, Tjitze van der Land, Yuanke Liang, Jianwu Sun, Amalia Dolga, Marleen Kamperman, Patrick van Rijn and Frank A. E. Kruyt

Int. J. Mol. Sci. 2022, 23(12), 6520; https://doi.org/10.3390/ijms23126520 - 10 Jun 2022

Cited by 4 | Viewed by 2648

Abstract

Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults. In addition to genetic causes, the tumor microenvironment (TME), including stiffening of the extracellular matrix (ECM), is a main driver of GBM progression. Mechano-transduction and the unfolded protein response (UPR) are essential for tumor-cell adaptation to harsh TME conditions. Here, we studied the effect of a variable stiff ECM on the morphology and malignant properties of GBM stem cells (GSCs) and, moreover, examined the possible involvement of the UPR sensor PERK herein. For this, stiffness-tunable human blood plasma (HBP)/alginate hydrogels were generated to mimic ECM stiffening. GSCs showed stiffness-dependent adaptation characterized by elongated morphology, increased proliferation, and motility which was accompanied by F-Actin cytoskeletal remodeling. Interestingly, in PERK-deficient GSCs, stiffness adaptation was severely impaired, which was evidenced by low F-Actin levels, the absence of F-Actin remodeling, and decreased cell proliferation and migration. This impairment could be linked with Filamin-A (FLN-A) expression, a known interactor of PERK, which was strongly reduced in PERK-deficient GSCs. In conclusion, we identified a novel PERK/FLNA/F-Actin mechano-adaptive mechanism and found a new function for PERK in the cellular adaptation to ECM stiffening. Full article

(This article belongs to the Special Issue Study of Endoplasmic Reticulum Stress and Unfolded Protein Response)

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13 pages, 881 KiB

Open AccessHypothesis

Increasing Stress to Induce Apoptosis in Pancreatic Cancer via the Unfolded Protein Response (UPR)

by Gehan Botrus, Richard M. Miller, Pedro Luiz Serrano Uson Junior, Geoffrey Kannan, Haiyong Han and Daniel D. Von Hoff

Int. J. Mol. Sci. 2023, 24(1), 577; https://doi.org/10.3390/ijms24010577 - 29 Dec 2022

Cited by 9 | Viewed by 2739

Abstract

High rates of cell proliferation and protein synthesis in pancreatic cancer are among many factors leading to endoplasmic reticulum (ER) stress. To restore cellular homeostasis, the unfolded protein response (UPR) activates as an adaptive mechanism through either the IRE1

α

, PERK, or [...] Read more.

α

, PERK, or ATF6 pathways to reduce the translational load and process unfolded proteins, thus enabling tumor cells to proliferate. Under severe and prolonged ER stress, however, the UPR may promote adaptation, senescence, or apoptosis under these same pathways if homeostasis is not restored. In this review, we present evidence that high levels of ER stress and UPR activation are present in pancreatic cancer. We detail the mechanisms by which compounds activate one or many of the three arms of the UPR and effectuate downstream apoptosis and examine available data on the pre-clinical and clinical-phase ER stress inducers with the potential for anti-tumor efficacy in pancreatic cancer. Finally, we hypothesize a potential new approach to targeting pancreatic cancer by increasing levels of ER stress and UPR activation to incite apoptotic cell death. Full article

(This article belongs to the Special Issue Study of Endoplasmic Reticulum Stress and Unfolded Protein Response)

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