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Endoplasmic Reticulum Stress and Unfolded Protein Response 2.0
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Endoplasmic Reticulum Stress and Unfolded Protein Response 2.0

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 July 2020) | Viewed by 23499

Special Issue Editor

Prof. Ireneusz Majsterek

E-Mail Website
Guest Editor
Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Lodz, Poland
Interests: DNA damage and repair; kinases inhibitors; Unfolded Protein Response; eye disease
Special Issues, Collections and Topics in MDPI journals

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. Ireneusz Majsterek
Guest Editor

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 (5 papers)

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Research

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18 pages, 4744 KiB  
Article
Misfolding of Lysosomal α-Galactosidase a in a Fly Model and Its Alleviation by the Pharmacological Chaperone Migalastat
by Hila Braunstein, Maria Papazian, Gali Maor, Jan Lukas, Arndt Rolfs and Mia Horowitz
Int. J. Mol. Sci. 2020, 21(19), 7397; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197397 - 07 Oct 2020
Cited by 5 | Viewed by 2804
Abstract
Fabry disease, an X-linked recessive lysosomal disease, results from mutations in the GLA gene encoding lysosomal α-galactosidase A (α-Gal A). Due to these mutations, there is accumulation of globotriaosylceramide (GL-3) in plasma and in a wide range of cells throughout the body. Like [...] Read more.
Fabry disease, an X-linked recessive lysosomal disease, results from mutations in the GLA gene encoding lysosomal α-galactosidase A (α-Gal A). Due to these mutations, there is accumulation of globotriaosylceramide (GL-3) in plasma and in a wide range of cells throughout the body. Like other lysosomal enzymes, α-Gal A is synthesized on endoplasmic reticulum (ER) bound polyribosomes, and upon entry into the ER it undergoes glycosylation and folding. It was previously suggested that α-Gal A variants are recognized as misfolded in the ER and undergo ER-associated degradation (ERAD). In the present study, we used Drosophila melanogaster to model misfolding of α-Gal A mutants. We did so by creating transgenic flies expressing mutant α-Gal A variants and assessing development of ER stress, activation of the ER stress response and their relief with a known α-Gal A chaperone, migalastat. Our results showed that the A156V and the A285D α-Gal A mutants underwent ER retention, which led to activation of unfolded protein response (UPR) and ERAD. UPR could be alleviated by migalastat. When expressed in the fly’s dopaminergic cells, misfolding of α-Gal A and UPR activation led to death of these cells and to a shorter life span, which could be improved, in a mutation-dependent manner, by migalastat. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2.0)
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20 pages, 4895 KiB  
Article
A Fluorescence Polarization-Based High-Throughput Screen to Identify the First Small-Molecule Modulators of the Human Adenylyltransferase HYPE/FICD
by Ali Camara, Alyssa George, Evan Hebner, Anika Mahmood, Jashun Paluru and Seema Mattoo
Int. J. Mol. Sci. 2020, 21(19), 7128; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197128 - 27 Sep 2020
Cited by 5 | Viewed by 2979
Abstract
The covalent transfer of the AMP portion of ATP onto a target protein—termed adenylylation or AMPylation—by the human Fic protein HYPE/FICD has recently garnered attention as a key regulatory mechanism in endoplasmic reticulum homeostasis, neurodegeneration, and neurogenesis. As a central player in such [...] Read more.
The covalent transfer of the AMP portion of ATP onto a target protein—termed adenylylation or AMPylation—by the human Fic protein HYPE/FICD has recently garnered attention as a key regulatory mechanism in endoplasmic reticulum homeostasis, neurodegeneration, and neurogenesis. As a central player in such critical cellular events, high-throughput screening (HTS) efforts targeting HYPE-mediated AMPylation warrant investigation. Herein, we present a dual HTS assay for the simultaneous identification of small-molecule activators and inhibitors of HYPE AMPylation. Employing the fluorescence polarization of an ATP analog fluorophore—Fl-ATP—we developed and optimized an efficient, robust assay that monitors HYPE autoAMPylation and is amenable to automated, high-throughput processing of diverse chemical libraries. Challenging our pilot screen with compounds from the LOPAC, Spectrum, MEGx, and NATx libraries yielded 0.3% and 1% hit rates for HYPE activators and inhibitors, respectively. Further, these hits were assessed for dose-dependency and validated via orthogonal biochemical AMPylation assays. We thus present a high-quality HTS assay suitable for tracking HYPE’s enzymatic activity, and the resultant first small-molecule manipulators of HYPE-promoted autoAMPylation. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2.0)
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20 pages, 4058 KiB  
Article
Lercanidipine Synergistically Enhances Bortezomib Cytotoxicity in Cancer Cells via Enhanced Endoplasmic Reticulum Stress and Mitochondrial Ca2+ Overload
by A Reum Lee, Min Ji Seo, Jin Kim, Dong Min Lee, In Young Kim, Mi Jin Yoon, Hur Hoon and Kyeong Sook Choi
Int. J. Mol. Sci. 2019, 20(24), 6112; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246112 - 04 Dec 2019
Cited by 15 | Viewed by 3328
Abstract
The proteasome inhibitor (PI), bortezomib (Btz), is effective in treating multiple myeloma and mantle cell lymphoma, but not solid tumors. In this study, we show for the first time that lercanidipine (Ler), an antihypertensive drug, enhances the cytotoxicity of various PIs, including Btz, [...] Read more.
The proteasome inhibitor (PI), bortezomib (Btz), is effective in treating multiple myeloma and mantle cell lymphoma, but not solid tumors. In this study, we show for the first time that lercanidipine (Ler), an antihypertensive drug, enhances the cytotoxicity of various PIs, including Btz, carfilzomib, and ixazomib, in many solid tumor cell lines by inducing paraptosis, which is accompanied by severe vacuolation derived from the endoplasmic reticulum (ER) and mitochondria. We found that Ler potentiates Btz-mediated ER stress and ER dilation, possibly due to misfolded protein accumulation, in MDA-MB 435S cells. In addition, the combination of Btz and Ler triggers mitochondrial Ca2+ overload, critically contributing to mitochondrial dilation and subsequent paraptotic events, including mitochondrial membrane potential loss and ER dilation. Taken together, our results suggest that a combined regimen of PI and Ler may effectively kill cancer cells via structural and functional perturbations of the ER and mitochondria. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2.0)
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Review

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25 pages, 1987 KiB  
Review
Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases
by Rose Ghemrawi and Mostafa Khair
Int. J. Mol. Sci. 2020, 21(17), 6127; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176127 - 25 Aug 2020
Cited by 155 | Viewed by 11292
Abstract
The endoplasmic reticulum (ER) is an important organelle involved in protein quality control and cellular homeostasis. The accumulation of unfolded proteins leads to an ER stress, followed by an adaptive response via the activation of the unfolded protein response (UPR), PKR-like ER kinase [...] Read more.
The endoplasmic reticulum (ER) is an important organelle involved in protein quality control and cellular homeostasis. The accumulation of unfolded proteins leads to an ER stress, followed by an adaptive response via the activation of the unfolded protein response (UPR), PKR-like ER kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) and activating transcription factor 6 (ATF6) pathways. However, prolonged cell stress activates apoptosis signaling leading to cell death. Neuronal cells are particularly sensitive to protein misfolding, consequently ER and UPR dysfunctions were found to be involved in many neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and prions diseases, among others characterized by the accumulation and aggregation of misfolded proteins. Pharmacological UPR modulation in affected tissues may contribute to the treatment and prevention of neurodegeneration. The association between ER stress, UPR and neuropathology is well established. In this review, we provide up-to-date evidence of UPR activation in neurodegenerative disorders followed by therapeutic strategies targeting the UPR and ameliorating the toxic effects of protein unfolding and aggregation. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2.0)
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26 pages, 343 KiB  
Review
Impact of Endoplasmic Reticulum Stress in Otorhinolaryngologic Diseases
by Su Young Jung, Sung Su Kim and Seung Geun Yeo
Int. J. Mol. Sci. 2020, 21(11), 4121; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21114121 - 09 Jun 2020
Cited by 3 | Viewed by 2659
Abstract
The endoplasmic reticulum (ER) is an important organelle for normal cellular function and homeostasis in most living things. ER stress, which impairs ER function, occurs when the ER is overwhelmed by newly introduced immature proteins or when calcium in the ER is depleted. [...] Read more.
The endoplasmic reticulum (ER) is an important organelle for normal cellular function and homeostasis in most living things. ER stress, which impairs ER function, occurs when the ER is overwhelmed by newly introduced immature proteins or when calcium in the ER is depleted. A number of diseases are associated with ER stress, including otorhinolaryngological diseases. The relationship between ER stress and otorhinolaryngologic conditions has been the subject of investigation over the last decade. Among otologic diseases associated with ER stress are otitis media and hearing loss. In rhinologic diseases, chronic rhinosinusitis, allergic rhinitis, and obstructive sleep apnea are also significantly associated with ER stress. In this review, we provide a comprehensive overview of the relationship between ER stress and otorhinolaryngological diseases, focusing on the current state of knowledge and mechanisms that link ER stress and otorhinolaryngologic diseases. Full article
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2.0)
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