Reexamining the Function of Glutathione in Oxidative Protein Folding and Secretion

Delaunay‐Moisan, Agnès; Ponsero, Alise J.; Toledano, Michel B.

doi:10.1089/ars.2017.7148

Cited by 41 publications

(32 citation statements)

References 190 publications

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“…ER depletion of GSH by ectopic expression of Chac1 in the ER did not alter protein folding and the ER stress response as well. As elegantly discussed by Ponsero and Toledano , the Chac1 degradation of GSH supplies the dipeptide that contains cysteine thus potentially supporting the reductive function of GSH. Therefore, their data did not conclusively exclude a contribution of GSH in oxidative protein folding.…”

Section: Subcellular Compartmentalizationmentioning

confidence: 98%

Glutathione compartmentalization and its role in glutathionylation and other regulatory processes of cellular pathways

et al. 2018

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Glutathione is considered the major non‐protein low molecular weight modulator of redox processes and the most important thiol reducing agent of the cell. The biosynthesis of glutathione occurs in the cytosol from its constituent amino acids, but this tripeptide is also present in the most important cellular districts, such as mitochondria, nucleus, and endoplasmic reticulum, thus playing a central role in several metabolic pathways and cytoprotection mechanisms. Indeed, glutathione is involved in the modulation of various cellular processes and, not by chance, it is a ubiquitous determinant for redox signaling, xenobiotic detoxification, and regulation of cell cycle and death programs. The balance between its concentration and redox state is due to a complex series of interactions between biosynthesis, utilization, degradation, and transport. All these factors are of great importance to understand the significance of cellular redox balance and its relationship with physiological responses and pathological conditions. The purpose of this review is to give an overview on glutathione cellular compartmentalization. Information on its subcellular distribution provides a deeper understanding of glutathione‐dependent processes and reflects the importance of compartmentalization in the regulation of specific cellular pathways. © 2018 BioFactors, 45(2):152–168, 2019

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Section: Subcellular Compartmentalizationmentioning

confidence: 98%

Glutathione compartmentalization and its role in glutathionylation and other regulatory processes of cellular pathways

et al. 2018

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“…In vivo, Ero1β deficiency produces a phenotype of increased proinsulin entrapment in the ER, which is associated with lower β‐cell insulin content and reduced insulin secretion . Nevertheless, not all PDI family members require ERO1 to catalyse their reoxidation (although such reoxidation is thought necessary to allow PDI‐mediated substrate oxidation to continue), suggesting the possibility of alternative oxidative recycling pathways for PDI family members …”

Section: Dynamic Regulation Of the Er Environment In Repsonse To Succmentioning

confidence: 99%

“…Alternatively, ROS may also be generated as a consequence of a futile cycle of oxidizing and reducing glutathione (GS‐SG and GSH, for oxidized and reduced forms of glutathione, respectively). As a consequence, pancreatic β‐cells, bearing the large load of proinsulin that must assemble 3 disulphide bonds per molecule, may be more susceptible to ER protein misfolding in response to overactivity of various oxidative enzymes .…”

Section: Dynamic Regulation Of the Er Environment In Repsonse To Succmentioning

confidence: 99%

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Biosynthesis, structure, and folding of the insulin precursor protein

Liu

Weiss

Arunagiri

et al. 2018

Diabetes Obesity Metabolism

158

165

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Insulin synthesis in pancreatic β-cells is initiated as preproinsulin. Prevailing glucose concentrations, which oscillate pre- and postprandially, exert major dynamic variation in preproinsulin biosynthesis. Accompanying upregulated translation of the insulin precursor includes elements of the endoplasmic reticulum (ER) translocation apparatus linked to successful orientation of the signal peptide, translocation and signal peptide cleavage of preproinsulin-all of which are necessary to initiate the pathway of proper proinsulin folding. Evolutionary pressures on the primary structure of proinsulin itself have preserved the efficiency of folding ("foldability"), and remarkably, these evolutionary pressures are distinct from those protecting the ultimate biological activity of insulin. Proinsulin foldability is manifest in the ER, in which the local environment is designed to assist in the overall load of proinsulin folding and to favour its disulphide bond formation (while limiting misfolding), all of which is closely tuned to ER stress response pathways that have complex (beneficial, as well as potentially damaging) effects on pancreatic β-cells. Proinsulin misfolding may occur as a consequence of exuberant proinsulin biosynthetic load in the ER, proinsulin coding sequence mutations, or genetic predispositions that lead to an altered ER folding environment. Proinsulin misfolding is a phenotype that is very much linked to deficient insulin production and diabetes, as is seen in a variety of contexts: rodent models bearing proinsulin-misfolding mutants, human patients with Mutant INS-gene-induced Diabetes of Youth (MIDY), animal models and human patients bearing mutations in critical ER resident proteins, and, quite possibly, in more common variety type 2 diabetes.

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“…The oxidized form of glutathione (GSSG), which predominates 2 in the ER lumen compared to the cytosol, was formerly thought to reoxidize protein disulfide 3 isomerase (PDI) to promote ER disulfide bond formation. However, since the discovery of 4 alternative pathways for PDI reoxidation (Frand & Kaiser, 1999;Tu, Ho-Schleyer, Travers, & 5 Weissman, 2000; Zito, Melo, et al, 2010), the role of glutathione in the ER is now much less 6 clear (Delaunay-Moisan, Ponsero, & Toledano, 2017;Tsunoda et al, 2014). Whether elevated 7 GSSG might be beneficial to ER function under some cellular conditions but detrimental in 8 others is also unknown.…”

Section: Introduction 1mentioning

confidence: 99%

NADPH and glutathione redox link TCA cycle activity to endoplasmic reticulum stress

Gansemer

McCommis

Martino

et al. 2019

Preprint

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1 2 Endoplasmic reticulum (ER) stress is associated with dysregulated metabolism, but little is 3 known about how the ER responds to metabolic activity. Here, working primarily in mouse 4 hepatocytes, we show that decreasing the availability of substrate for the TCA cycle diminished 5 NADPH production and attenuated ER stress in a manner that depended on glutathione 6 oxidation. ER stress was also alleviated by impairing either TCA-dependent NADPH production 7 or Glutathione Reductase. Conversely, stimulating TCA activity favored NADPH production, 8 glutathione reduction, and ER stress. Validating these findings, we show that deletion of the 9 mitochondrial pyruvate carrier, which is known to decrease TCA cycle activity and protect the 10 liver from diet-induced injury, also diminished NADPH, elevated glutathione oxidation, and 11 alleviated ER stress. These results provide independent genetic evidence that mitochondrial 12 oxidative metabolism is linked to ER homeostasis. Our results demonstrate a novel pathway of 13 communication between mitochondria and the ER, through relay of redox metabolites. 14 15 16

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Reexamining the Function of Glutathione in Oxidative Protein Folding and Secretion

Cited by 41 publications

References 190 publications

Glutathione compartmentalization and its role in glutathionylation and other regulatory processes of cellular pathways

Glutathione compartmentalization and its role in glutathionylation and other regulatory processes of cellular pathways

Biosynthesis, structure, and folding of the insulin precursor protein

NADPH and glutathione redox link TCA cycle activity to endoplasmic reticulum stress

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