The mammalian cytosolic thioredoxin reductase pathway acts via a membrane protein to reduce ER-localised proteins

Cao, Xiaofei; Lilla, Sérgio; Cao, Zhenbo; Pringle, Marie Anne; Oka, Ojore; Robinson, Philip J.; Szmaja, Tomasz; Lith, Marcel van; Zanivan, Sara; Bulleid, Neil J.

doi:10.1242/jcs.241976

Cited by 19 publications

(17 citation statements)

References 48 publications

(67 reference statements)

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“…To reset PDIs for sequential rounds of client protein isomerization, ER oxidoreductin 1α (Ero1α) utilizes a highly regulated feedback loop of intramolecular disulfide switches involving glutathione disulfide (GSSG) and reduced glutathione (GSH) redox shuttles [ 123 , 124 , 125 ]. In addition to glutathione, thioredoxin also acts as an electron donor in the isomerization of disulfide bonds that reset PDIs [ 126 ], although the mechanisms regulating the transfer of reducing equivalents from the cytosol to the ER lumen is not well understood [ 126 , 127 ]. While the quantitative contribution of these two donor systems (glutathione and thioredoxin) to disulfide bond formation has yet to be determined, both mechanisms are regulated by NADPH-dependent enzymes, namely glutathione reductase and thioredoxin reductase, which are sensitive to fluctuations in mitochondrial metabolism [ 126 ].…”

Section: Metabolic Influence On β-Cell Er Redox Homeostasismentioning

confidence: 99%

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

et al. 2022

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Pancreatic islet β-cells exhibit tremendous plasticity for secretory adaptations that coordinate insulin production and release with nutritional demands. This essential feature of the β-cell can allow for compensatory changes that increase secretory output to overcome insulin resistance early in Type 2 diabetes (T2D). Nutrient-stimulated increases in proinsulin biosynthesis may initiate this β-cell adaptive compensation; however, the molecular regulators of secretory expansion that accommodate the increased biosynthetic burden of packaging and producing additional insulin granules, such as enhanced ER and Golgi functions, remain poorly defined. As these adaptive mechanisms fail and T2D progresses, the β-cell succumbs to metabolic defects resulting in alterations to glucose metabolism and a decline in nutrient-regulated secretory functions, including impaired proinsulin processing and a deficit in mature insulin-containing secretory granules. In this review, we will discuss how the adaptative plasticity of the pancreatic islet β-cell’s secretory program allows insulin production to be carefully matched with nutrient availability and peripheral cues for insulin signaling. Furthermore, we will highlight potential defects in the secretory pathway that limit or delay insulin granule biosynthesis, which may contribute to the decline in β-cell function during the pathogenesis of T2D.

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Section: Metabolic Influence On β-Cell Er Redox Homeostasismentioning

confidence: 99%

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

et al. 2022

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“…It is well established that reducing PDIs act on released substrates in the ER; however, can they also act on substrates at the co-translational stage? Disulfide rearrangements require reducing power, which originates in the cytosol [75] and transfers across the membrane via an unidentified transmembrane protein [76], for use by reducing PDIs such as ERdj5 [77] and ERp57 [78]. By controlling the activity of these pathways, disulfide rearrangements can be monitored in translation systems [50,75].…”

Section: Evidence For Disulfide Reduction and Rearrangements At The Cmentioning

confidence: 99%

Mechanisms of Disulfide Bond Formation in Nascent Polypeptides Entering the Secretory Pathway

Robinson

Bulleid

2020

Cells

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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.

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“…The effects of the Trx system extend to the ER, with cytosolic TrxR1 surprisingly being required for reducing non-native disulfides during oxidative folding in the ER ( Poet et al, 2017 ). Further analysis in an in vitro reconstituted system determined that an as-yet unidentified ER membrane protein or proteins are required for Trx and TrxR1 to exert their effects on ER disulfide reduction ( Cao et al, 2020 ; Van Lith et al, 2021 ). Its proteinaceous nature was determined by showing that the ability of Trx to mediate the reduction of lumenal components was protease-sensitive.…”

Section: Pathways Linking Reduced Nicotinamide Adenine Dinucleotide P...mentioning

confidence: 99%

Pathways Linking Nicotinamide Adenine Dinucleotide Phosphate Production to Endoplasmic Reticulum Protein Oxidation and Stress

Gansemer

Rutkowski

2022

Front. Mol. Biosci.

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The endoplasmic reticulum (ER) lumen is highly oxidizing compared to other subcellular compartments, and maintaining the appropriate levels of oxidizing and reducing equivalents is essential to ER function. Both protein oxidation itself and other essential ER processes, such as the degradation of misfolded proteins and the sequestration of cellular calcium, are tuned to the ER redox state. Simultaneously, nutrients are oxidized in the cytosol and mitochondria to power ATP generation, reductive biosynthesis, and defense against reactive oxygen species. These parallel needs for protein oxidation in the ER and nutrient oxidation in the cytosol and mitochondria raise the possibility that the two processes compete for electron acceptors, even though they occur in separate cellular compartments. A key molecule central to both processes is NADPH, which is produced by reduction of NADP+ during nutrient catabolism and which in turn drives the reduction of components such as glutathione and thioredoxin that influence the redox potential in the ER lumen. For this reason, NADPH might serve as a mediator linking metabolic activity to ER homeostasis and stress, and represent a novel form of mitochondria-to-ER communication. In this review, we discuss oxidative protein folding in the ER, NADPH generation by the major pathways that mediate it, and ER-localized systems that can link the two processes to connect ER function to metabolic activity.

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The mammalian cytosolic thioredoxin reductase pathway acts via a membrane protein to reduce ER-localised proteins

Cited by 19 publications

References 48 publications

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production

Mechanisms of Disulfide Bond Formation in Nascent Polypeptides Entering the Secretory Pathway

Pathways Linking Nicotinamide Adenine Dinucleotide Phosphate Production to Endoplasmic Reticulum Protein Oxidation and Stress

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