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Physiological and Pathological Aspects of Unfolded Protein Response
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Physiological and Pathological Aspects of Unfolded Protein Response

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

Deadline for manuscript submissions: closed (15 March 2021) | Viewed by 20001

Special Issue Editor

Dr. Michele Sallese

E-Mail Website
Guest Editor
Department of Medical, Oral and Biotechnological Sciences, ‘G. d’Annunzio’ University of Chieti–Pescara, 66100 Chieti, Italy
Interests: misfolding diseases; unfolded protein response; membrane trafficking; gluten related disorders; gene expression; cell signaling; cell invasion
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Protein homeostasis, or proteostasis, is a dynamic process involving the continuous degradation and replacement of damaged proteins with newly synthesized proteins. Proteins are synthesised by ribosomes as unstructured polypeptides when, thanks to dedicated folding machinery involving high energy expenditure, the polypeptides acquire the correct three-dimensional structure. Indeed, some proteins are inherently difficult to fold and the fraction of them that remain misshapen has to be discarded. Meanwhile, some polypeptides that carry point mutations cannot be folded at all. Mutations can also affect and damage the folding machinery itself.

Accumulation of unfolded proteins activates the unfolded protein response (UPR), a signalling and transcriptional programme aimed at coping with cellular stress due to misfolding. UPR involves three ER stress sensors, namely PERK, IRE1, and ATF6, which trigger various molecular responses with the aim of reducing protein synthesis and enhancing folding and/or degradation of misfolded proteins. If these measures do not allow the stress to be overcome, the UPR activates apoptotic cell death.

Notably, a number of human diseases involve an alteration of proteostasis. The loss of important functions and/or toxic gains of function are the main mechanisms of these misfolding diseases. In the first group of diseases, misshapen proteins never reach their final destination because the ER quality control systems recognize and direct them to disposal (for example, via proteasome or autophagolysosome). In the second group, unfolded proteins aggregate and lead to cellular toxicity through different mechanisms. To date, the therapeutic options for misfolding diseases are rather limited. Pioneering studies have shown that neurodegenerative diseases can have some benefits from inhibiting or activating the UPR, depending on the specific disease. However, it is absolutely necessary to study more effective strategies to improve the quality of life of these patients.

This overview is not exhaustive but covers possible topics welcome in this Special Issue. I am confident that a number of additional aspects on human diseases involving misfolded proteins will be proposed.

Both original articles, reviews and commentaries are welcome.

Dr. Michele Sallese
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

  • human diseases
  • protein folding machinery
  • unfolded protein response
  • ER associated degradation
  • ER-to-lysosome-associated degradation
  • toxic gain-of-function
  • pathogenic pathways
  • innovative therapeutic strategies

Related Special Issue

Published Papers (5 papers)

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Research

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24 pages, 6337 KiB  
Article
Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways
by Rebeka Popovic, Ivana Celardo, Yizhou Yu, Ana C. Costa, Samantha H. Y. Loh and L. Miguel Martins
Int. J. Mol. Sci. 2021, 22(9), 4598; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094598 - 27 Apr 2021
Cited by 4 | Viewed by 3596
Abstract
In Drosophila, endoplasmic reticulum (ER) stress activates the protein kinase R-like endoplasmic reticulum kinase (dPerk). dPerk can also be activated by defective mitochondria in fly models of Parkinson’s disease caused by mutations in pink1 or parkin. The Perk branch of the [...] Read more.
In Drosophila, endoplasmic reticulum (ER) stress activates the protein kinase R-like endoplasmic reticulum kinase (dPerk). dPerk can also be activated by defective mitochondria in fly models of Parkinson’s disease caused by mutations in pink1 or parkin. The Perk branch of the unfolded protein response (UPR) has emerged as a major toxic process in neurodegenerative disorders causing a chronic reduction in vital proteins and neuronal death. In this study, we combined microarray analysis and quantitative proteomics analysis in adult flies overexpressing dPerk to investigate the relationship between the transcriptional and translational response to dPerk activation. We identified tribbles and Heat shock protein 22 as two novel Drosophila activating transcription factor 4 (dAtf4) regulated transcripts. Using a combined bioinformatics tool kit, we demonstrated that the activation of dPerk leads to translational repression of mitochondrial proteins associated with glutathione and nucleotide metabolism, calcium signalling and iron-sulphur cluster biosynthesis. Further efforts to enhance these translationally repressed dPerk targets might offer protection against Perk toxicity. Full article
(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response)
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13 pages, 2429 KiB  
Article
Tau Is Truncated in Five Regions of the Normal Adult Human Brain
by Michael G. Friedrich, Amanda Skora, Sarah E. Hancock, Todd W. Mitchell, Paul L. Else and Roger J. W. Truscott
Int. J. Mol. Sci. 2021, 22(7), 3521; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073521 - 29 Mar 2021
Cited by 10 | Viewed by 2668
Abstract
The truncation of Tau is thought to be important in promoting aggregation, with this feature characterising the pathology of dementias such as Alzheimer disease. Antibodies to the C-terminal and N-terminal regions of Tau were employed to examine Tau cleavage in five human brain [...] Read more.
The truncation of Tau is thought to be important in promoting aggregation, with this feature characterising the pathology of dementias such as Alzheimer disease. Antibodies to the C-terminal and N-terminal regions of Tau were employed to examine Tau cleavage in five human brain regions: the entorhinal cortex, prefrontal cortex, motor cortex, hippocampus, and cerebellum. These were obtained from normal subjects ranging in age from 18 to 104 years. Tau fragments of approximately 40 kDa and 45 kDa with an intact N-terminus retained were found in soluble and insoluble brain fractions. In addition, smaller C-terminal Tau fragments ranging in mass from 17 kDa to 25 kDa were also detected. These findings are consistent with significant Tau cleavage taking place in brain regions from 18 years onwards. It appears that site-specific cleavage of Tau is widespread in the normal human brain, and that large Tau fragments that contain the N-terminus, as well as shorter C-terminal Tau fragments, are present in brain cells across the age range. Full article
(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response)
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18 pages, 4572 KiB  
Article
Role of the ROS-JNK Signaling Pathway in Hypoxia-Induced Atrial Fibrotic Responses in HL-1 Cardiomyocytes
by Chin-Feng Tsai, Shun-Fa Yang, Chien-Hsien Lo, Hsiao-Ju Chu and Kwo-Chang Ueng
Int. J. Mol. Sci. 2021, 22(6), 3249; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22063249 - 23 Mar 2021
Cited by 13 | Viewed by 2953
Abstract
By promoting atrial structural remodeling, atrial hypoxia contributes to the development of the atrial fibrillation substrate. Our study aimed to investigate the modulatory effect of hypoxia on profibrotic activity in cultured HL-1 cardiomyocytes and explore the possible signaling transduction mechanisms of profibrotic activity [...] Read more.
By promoting atrial structural remodeling, atrial hypoxia contributes to the development of the atrial fibrillation substrate. Our study aimed to investigate the modulatory effect of hypoxia on profibrotic activity in cultured HL-1 cardiomyocytes and explore the possible signaling transduction mechanisms of profibrotic activity in vitro. Hypoxia (1% O2) significantly and time-dependently increased the expression of hypoxia-inducible factor (HIF)-1α and fibrotic marker proteins collagen I and III (COL1A and COL3A), transforming growth factor (TGF)-β1 and α-smooth muscle actin (SMA). Western blot or immunohistochemistry analysis showed that hypoxia-induced increase in COL1A and COL3A was significantly attenuated by the addition of SP600125 (a specific c-Jun N-terminal kinase [JNK] inhibitor) or expression of dominant-negative JNK before hypoxia treatment. The inhibition of hypoxia-activated phosphorylation of JNK signal components (JNK, MKK4, nuclear c-Jun and ATF-2) by pre-treatment with SP600125 could suppress hypoxia-stimulated HIF-1α upregulation and fibrotic marker proteins expression. Hypoxia significantly increased reactive oxygen species (ROS) production in cultured HL-1 atrial cells. Pre-treatment with N-acetylcysteine significantly abrogated the expression of nuclear HIF-1α, JNK transduction components and fibrotic marker proteins. Taken together, these findings indicated that the hypoxia-induced atrial profibrotic response occurs mainly via the ROS/JNK pathway, its downstream upregulation of HIF-1α and c-Jun/ATF2 phosphorylation and nuclear translocation to up-regulate the expression of fibrosis-related proteins (COL1A, COL3A, TGF-β1 and α-SMA). Our result suggests that suppression of ROS/JNK signaling pathway is a critical mechanism for developing a novel therapeutic strategy against atrial fibrillation. Full article
(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response)
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Review

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14 pages, 840 KiB  
Review
The Function of KDEL Receptors as UPR Genes in Disease
by Emily S. Wires, Kathleen A. Trychta, Lacey M. Kennedy and Brandon K. Harvey
Int. J. Mol. Sci. 2021, 22(11), 5436; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115436 - 21 May 2021
Cited by 10 | Viewed by 5251
Abstract
The KDEL receptor retrieval pathway is essential for maintaining resident proteins in the endoplasmic reticulum (ER) lumen. ER resident proteins serve a variety of functions, including protein folding and maturation. Perturbations to the lumenal ER microenvironment, such as calcium depletion, can cause protein [...] Read more.
The KDEL receptor retrieval pathway is essential for maintaining resident proteins in the endoplasmic reticulum (ER) lumen. ER resident proteins serve a variety of functions, including protein folding and maturation. Perturbations to the lumenal ER microenvironment, such as calcium depletion, can cause protein misfolding and activation of the unfolded protein response (UPR). Additionally, ER resident proteins are secreted from the cell by overwhelming the KDEL receptor retrieval pathway. Recent data show that KDEL receptors are also activated during the UPR through the IRE1/XBP1 signaling pathway as an adaptive response to cellular stress set forth to reduce the loss of ER resident proteins. This review will discuss the emerging connection between UPR activation and KDEL receptors as it pertains to ER proteostasis and disease states. Full article
(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response)
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24 pages, 1806 KiB  
Review
Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly
by Rubén Hervás and Javier Oroz
Int. J. Mol. Sci. 2020, 21(23), 9186; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239186 - 02 Dec 2020
Cited by 18 | Viewed by 4745
Abstract
Age-dependent alterations in the proteostasis network are crucial in the progress of prevalent neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, or amyotrophic lateral sclerosis, which are characterized by the presence of insoluble protein deposits in degenerating neurons. Because molecular chaperones deter misfolded protein aggregation, [...] Read more.
Age-dependent alterations in the proteostasis network are crucial in the progress of prevalent neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, or amyotrophic lateral sclerosis, which are characterized by the presence of insoluble protein deposits in degenerating neurons. Because molecular chaperones deter misfolded protein aggregation, regulate functional phase separation, and even dissolve noxious aggregates, they are considered major sentinels impeding the molecular processes that lead to cell damage in the course of these diseases. Indeed, members of the chaperome, such as molecular chaperones and co-chaperones, are increasingly recognized as therapeutic targets for the development of treatments against degenerative proteinopathies. Chaperones must recognize diverse toxic clients of different orders (soluble proteins, biomolecular condensates, organized protein aggregates). It is therefore critical to understand the basis of the selective chaperone recognition to discern the mechanisms of action of chaperones in protein conformational diseases. This review aimed to define the selective interplay between chaperones and toxic client proteins and the basis for the protective role of these interactions. The presence and availability of chaperone recognition motifs in soluble proteins and in insoluble aggregates, both functional and pathogenic, are discussed. Finally, the formation of aberrant (pro-toxic) chaperone complexes will also be disclosed. Full article
(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response)
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