Special Issue "Redox-dependent ER processes"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Organelle Function".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 11530

Special Issue Editor

Prof. Dr. Gerardo Z. Lederkremer
E-Mail Website
Guest Editor
School of Molecular Cell Biology and Biotechnology, Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel
Interests: ER quality control; ERAD; glycoprotein misfolding; ER stress; UPR; protein aggregation; Huntington disease; neurodegenerative diseases
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Special Issue Information

Dear Colleagues,

Since the discovery of its oxidizing environment, much attention has been dedicated to understanding the redox-dependent processes taking place in the ER. In spite of this, the mechanisms of redox regulation are still not entirely elucidated, and the functions have been characterized for only a handful of the about 20 oxidoreductases involved in disulfide oxidation, reduction and isomerization during protein folding in the ER. Recently identified functions include regulation of ER folding and quality control machineries. This Special Issue seeks reviews and original papers covering a wide range of topics related to redox-dependent ER processes, such as redox dynamics and maintenance, and thioredoxin-like protein involvement in protein folding and other mechanisms in the ER.

Prof. Gerardo Z. Lederkremer
Guest Editor

Manuscript Submission Information

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Keywords

  • endoplasmic reticulum
  • oxidoreductase
  • thioredoxin-like
  • PDI
  • ERO1
  • glutathione
  • disulfide bonding
  • ERAD

Published Papers (6 papers)

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Research

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Article
Protein Translocation Acquires Substrate Selectivity Through ER Stress-Induced Reassembly of Translocon Auxiliary Components
Cells 2020, 9(2), 518; https://doi.org/10.3390/cells9020518 - 24 Feb 2020
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Abstract
Protein import across the endoplasmic reticulum membrane is physiologically regulated in a substrate-selective manner to ensure the protection of stressed ER from the overload of misfolded proteins. However, it is poorly understood how different types of substrates are accurately distinguished and disqualified during [...] Read more.
Protein import across the endoplasmic reticulum membrane is physiologically regulated in a substrate-selective manner to ensure the protection of stressed ER from the overload of misfolded proteins. However, it is poorly understood how different types of substrates are accurately distinguished and disqualified during translocational regulation. In this study, we found poorly assembled translocon-associated protein (TRAP) complexes in stressed ER. Immunoaffinity purification identified calnexin in the TRAP complex in which poor assembly inhibited membrane insertion of the prion protein (PrP) in a transmembrane sequence-selective manner, through translocational regulation. This reaction was induced selectively by redox perturbation, rather than calcium depletion, in the ER. The liberation of ERp57 from calnexin appeared to be the reason for the redox sensitivity. Stress-independent disruption of the TRAP complex prevented a pathogenic transmembrane form of PrP (ctmPrP) from accumulating in the ER. This study uncovered a previously unappreciated role for calnexin in assisting the redox-sensitive function of the TRAP complex and provided insights into the ER stress-induced reassembly of translocon auxiliary components as a key mechanism by which protein translocation acquires substrate selectivity. Full article
(This article belongs to the Special Issue Redox-dependent ER processes)
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Review

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Review
Intracellular Sources of ROS/H2O2 in Health and Neurodegeneration: Spotlight on Endoplasmic Reticulum
Cells 2021, 10(2), 233; https://doi.org/10.3390/cells10020233 - 25 Jan 2021
Cited by 24 | Viewed by 2483
Abstract
Reactive oxygen species (ROS) are produced continuously throughout the cell as products of various redox reactions. Yet these products function as important signal messengers, acting through oxidation of specific target factors. Whilst excess ROS production has the potential to induce oxidative stress, physiological [...] Read more.
Reactive oxygen species (ROS) are produced continuously throughout the cell as products of various redox reactions. Yet these products function as important signal messengers, acting through oxidation of specific target factors. Whilst excess ROS production has the potential to induce oxidative stress, physiological roles of ROS are supported by a spatiotemporal equilibrium between ROS producers and scavengers such as antioxidative enzymes. In the endoplasmic reticulum (ER), hydrogen peroxide (H2O2), a non-radical ROS, is produced through the process of oxidative folding. Utilisation and dysregulation of H2O2, in particular that generated in the ER, affects not only cellular homeostasis but also the longevity of organisms. ROS dysregulation has been implicated in various pathologies including dementia and other neurodegenerative diseases, sanctioning a field of research that strives to better understand cell-intrinsic ROS production. Here we review the organelle-specific ROS-generating and consuming pathways, providing evidence that the ER is a major contributing source of potentially pathologic ROS. Full article
(This article belongs to the Special Issue Redox-dependent ER processes)
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Review
Pathways for Sensing and Responding to Hydrogen Peroxide at the Endoplasmic Reticulum
Cells 2020, 9(10), 2314; https://doi.org/10.3390/cells9102314 - 18 Oct 2020
Cited by 10 | Viewed by 1775
Abstract
The endoplasmic reticulum (ER) has emerged as a source of hydrogen peroxide (H2O2) and a hub for peroxide-based signaling events. Here we outline cellular sources of ER-localized peroxide, including sources within and near the ER. Focusing on three ER-localized [...] Read more.
The endoplasmic reticulum (ER) has emerged as a source of hydrogen peroxide (H2O2) and a hub for peroxide-based signaling events. Here we outline cellular sources of ER-localized peroxide, including sources within and near the ER. Focusing on three ER-localized proteins—the molecular chaperone BiP, the transmembrane stress-sensor IRE1, and the calcium pump SERCA2—we discuss how post-translational modification of protein cysteines by H2O2 can alter ER activities. We review how changed activities for these three proteins upon oxidation can modulate signaling events, and also how cysteine oxidation can serve to limit the cellular damage that is most often associated with elevated peroxide levels. Full article
(This article belongs to the Special Issue Redox-dependent ER processes)
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Review
Oxidoreductases in Glycoprotein Glycosylation, Folding, and ERAD
Cells 2020, 9(9), 2138; https://doi.org/10.3390/cells9092138 - 22 Sep 2020
Cited by 8 | Viewed by 1788
Abstract
N-linked glycosylation and sugar chain processing, as well as disulfide bond formation, are among the most common post-translational protein modifications taking place in the endoplasmic reticulum (ER). They are essential modifications that are required for membrane and secretory proteins to achieve their correct [...] Read more.
N-linked glycosylation and sugar chain processing, as well as disulfide bond formation, are among the most common post-translational protein modifications taking place in the endoplasmic reticulum (ER). They are essential modifications that are required for membrane and secretory proteins to achieve their correct folding and native structure. Several oxidoreductases responsible for disulfide bond formation, isomerization, and reduction have been shown to form stable, functional complexes with enzymes and chaperones that are involved in the initial addition of an N-glycan and in folding and quality control of the glycoproteins. Some of these oxidoreductases are selenoproteins. Recent studies also implicate glycan machinery–oxidoreductase complexes in the recognition and processing of misfolded glycoproteins and their reduction and targeting to ER-associated degradation. This review focuses on the intriguing cooperation between the glycoprotein-specific cell machineries and ER oxidoreductases, and highlights open questions regarding the functions of many members of this large family. Full article
(This article belongs to the Special Issue Redox-dependent ER processes)
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Review
Thioredoxin-Related Transmembrane Proteins: TMX1 and Little Brothers TMX2, TMX3, TMX4 and TMX5
Cells 2020, 9(9), 2000; https://doi.org/10.3390/cells9092000 - 31 Aug 2020
Cited by 7 | Viewed by 1625
Abstract
The endoplasmic reticulum (ER) is site of synthesis and maturation of membrane and secretory proteins in eukaryotic cells. The ER contains more than 20 members of the Protein Disulfide Isomerase (PDI) family. These enzymes regulate formation, isomerization and disassembly of covalent bonds between [...] Read more.
The endoplasmic reticulum (ER) is site of synthesis and maturation of membrane and secretory proteins in eukaryotic cells. The ER contains more than 20 members of the Protein Disulfide Isomerase (PDI) family. These enzymes regulate formation, isomerization and disassembly of covalent bonds between cysteine residues. As such, PDIs ensure protein folding, which is required to attain functional and transport-competent structure, and protein unfolding, which facilitates dislocation of defective gene products across the ER membrane for ER-associated degradation (ERAD). The PDI family includes over a dozen of soluble members and few membrane-bound ones. Among these latter, there are five PDIs grouped in the thioredoxin-related transmembrane (TMX) protein family. In this review, we summarize the current knowledge on TMX1, TMX2, TMX3, TMX4 and TMX5, their structural features, regulation and roles in biogenesis and control of the mammalian cell’s proteome. Full article
(This article belongs to the Special Issue Redox-dependent ER processes)
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Review
Mechanisms of Disulfide Bond Formation in Nascent Polypeptides Entering the Secretory Pathway
Cells 2020, 9(9), 1994; https://doi.org/10.3390/cells9091994 - 29 Aug 2020
Cited by 12 | Viewed by 1990
Abstract
Disulfide bonds are an abundant feature of proteins across all domains of life that are important for structure, stability, and function. In eukaryotic cells, a major site of disulfide bond formation is the endoplasmic reticulum (ER). How cysteines correctly pair during polypeptide folding [...] Read more.
Disulfide bonds are an abundant feature of proteins across all domains of life that are important for structure, stability, and function. In eukaryotic cells, a major site of disulfide bond formation is the endoplasmic reticulum (ER). How cysteines correctly pair during polypeptide folding to form the native disulfide bond pattern is a complex problem that is not fully understood. In this paper, the evidence for different folding mechanisms involved in ER-localised disulfide bond formation is reviewed with emphasis on events that occur during ER entry. Disulfide formation in nascent polypeptides is discussed with focus on (i) its mechanistic relationship with conformational folding, (ii) evidence for its occurrence at the co-translational stage during ER entry, and (iii) the role of protein disulfide isomerase (PDI) family members. This review highlights the complex array of cellular processes that influence disulfide bond formation and identifies key questions that need to be addressed to further understand this fundamental process. Full article
(This article belongs to the Special Issue Redox-dependent ER processes)
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