Vitamin K epoxide reductase contributes to protein disulfide formation and redox homeostasis within the endoplasmic reticulum

Rutkevich, Lori A.; Williams, David B.

doi:10.1091/mbc.e12-02-0102

Cited by 70 publications

(73 citation statements)

References 58 publications

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“…ER re-oxidation following the washout of DTT is a rapid process, which takes less than five minutes and depends on Ero1a (Appenzeller-Herzog et al, 2010;van Lith et al, 2011;Rutkevich and Williams, 2012). Although PDI is the principal substrate of Ero1a (Inaba et al, 2010;Ramming and Appenzeller-Herzog, 2012), evidence exists that, unlike at steady state (see above), other family members such as ERp57 are also oxidized via Ero1a during early time points of recovery after DTT (when Ero1a is maximally active) (Appenzeller-Herzog et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum: Reduced and oxidized glutathione revisited

Birk¹,

Meyer²,

Aller³

et al. 2013

Journal of Cell Science

140

152

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SummaryThe reducing power of glutathione, expressed by its reduction potential E GSH , is an accepted measure for redox conditions in a given cell compartment. In the endoplasmic reticulum (ER), E GSH is less reducing than elsewhere in the cell. However, attempts to determine E GSH (ER) have been inconsistent and based on ineligible assumptions. Using a codon-optimized and evidently glutathione-specific glutaredoxin-coupled redox-sensitive green fluorescent protein (roGFP) variant, we determined E GSH (ER) in HeLa cells as 220864 mV (at pH 7.0). At variance with existing models, this is not oxidizing enough to maintain the known redox state of protein disulfide isomerase family enzymes. Live-cell microscopy confirmed ER hypo-oxidation upon inhibition of ER Ca 2+ import. Conversely, stressing the ER with a glycosylation inhibitor did not lead to more reducing conditions, as reported for yeast. These results, which for the first time establish the oxidative capacity of glutathione in the ER, illustrate a context-dependent interplay between ER stress and E GSH (ER). The reported development of ER-localized E GSH sensors will enable more targeted in vivo redox analyses in ERrelated disorders.

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Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum: Reduced and oxidized glutathione revisited

Birk¹,

Meyer²,

Aller³

et al. 2013

Journal of Cell Science

140

152

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“…Further research is needed to 14 explore the regulation of luminal FAD pool in the ER [103] and its physiological implications. VKOR activities resulted in cell death [105]. Thus, the PDI -VKOR -oxygen electron transfer chain contributes significantly to the oxidative folding.…”

Section: Flavin Nucleotidesmentioning

confidence: 99%

Composition of the redox environment of the endoplasmic reticulum and sources of hydrogen peroxide

Margittai

Enyedi

Csala

et al. 2015

Free Radical Biology and Medicine

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“…The relative contribution of this pathway to disulfide formation is not clear but it is known that combined knockdown of Ero1, PrxIV, and VKOR compromises disulfide formation and causes cell death in a mammalian cell culture system (Rutkevich and Williams 2012).…”

Section: Disulfide Formation In the Ermentioning

confidence: 99%

Disulfide Bond Formation in the Mammalian Endoplasmic Reticulum

Bulleid

2012

Cold Spring Harbor Perspectives in Biology

112

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The formation of disulfide bonds between cysteine residues occurs during the folding of many proteins that enter the secretory pathway. As the polypeptide chain collapses, cysteines brought into proximity can form covalent linkages during a process catalyzed by members of the protein disulfide isomerase family. There are multiple pathways in mammalian cells to ensure disulfides are introduced into proteins. Common requirements for this process include a disulfide exchange protein and a protein oxidase capable of forming disulfides de novo. In addition, any incorrect disulfides formed during the normal folding pathway are removed in a process involving disulfide exchange. The pathway for the reduction of disulfides remains poorly characterized. This work will cover the current knowledge in the field and discuss areas for future investigation.

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Vitamin K epoxide reductase contributes to protein disulfide formation and redox homeostasis within the endoplasmic reticulum

Cited by 70 publications

References 58 publications

Endoplasmic reticulum: Reduced and oxidized glutathione revisited

Endoplasmic reticulum: Reduced and oxidized glutathione revisited

Composition of the redox environment of the endoplasmic reticulum and sources of hydrogen peroxide

Disulfide Bond Formation in the Mammalian Endoplasmic Reticulum

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