Reduction-Reoxidation Cycles Contribute to Catalysis of disulfide Isomerization by Protein-disulfide Isomerase

Schwaller, Melissa; Wilkinson, Bonney; Gilbert, Hiram F.

doi:10.1074/jbc.m211036200

Cited by 131 publications

(100 citation statements)

References 26 publications

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“…The PDI family is composed of at least 20 proteins involved in the folding and maturation of ER proteins via disulfide formation and cyclic oxidation/reduction. 28 Little information is available on the specific role, abundance and regulation of each isoform, but they are described as Ca 2 þ -binding proteins. As a result, it was tempting to hypothesize that their overexpression might lead to a blockade of Ca 2 þ in the ER and that a defect in Ca 2 þ fluxes between ER and mitochondria could prevent MMP induction upon CDDP treatment.…”

Section: Discussionmentioning

confidence: 99%

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The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma

et al. 2014

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Intrinsic and acquired chemoresistance are frequent causes of cancer eradication failure. Thus, long-term cis-diaminedichloroplatine(II) (CDDP) or cisplatin treatment is known to promote tumor cell resistance to apoptosis induction via multiple mechanisms involving gene expression modulation of oncogenes, tumor suppressors and blockade of pro-apoptotic mitochondrial membrane permeabilization. Here, we demonstrate that CDDP-resistant non-small lung cancer cells undergo profound remodeling of their endoplasmic reticulum (ER) proteome (480 proteins identified by proteomics) and exhibit a dramatic overexpression of two protein disulfide isomerases, PDIA4 and PDIA6, without any alteration in ER-cytosol Ca 2 þ fluxes. Using pharmacological and genetic inhibition, we show that inactivation of both proteins directly stimulates CDDP-induced cell death by different cellular signaling pathways. PDIA4 inactivation restores a classical mitochondrial apoptosis pathway, while knockdown of PDIA6 favors a non-canonical cell death pathway sharing some necroptosis features. Overexpression of both proteins has also been found in lung adenocarcinoma patients, suggesting a clinical importance of these proteins in chemoresistance.

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Section: Discussionmentioning

confidence: 99%

“…PDI proteins are soluble Ca 2 þ -binding chaperones containing thioredoxin-like domains, 28 but little information is available on physiological PDIA4 and PDIA6 activity. Therefore, we determined whether changes in PDIA4 and PDIA6 protein levels lead to a change in cellular PDI enzymatic activity.…”

Section: Wt R2mentioning

confidence: 99%

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma

et al. 2014

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“…Detection of PDI Radicals with Ac-Tempo-According to previous reports, Ac-Tempo, a paramagnetic nonfluorescent conjugate of nitroxide and acridine, interacts with glutathionyl radicals resulting in increased fluorescence of the acridine moiety of Ac-Tempo (22). Ac-Tempo concentration was determined by measuring absorbance at 359 nm (⑀ ϭ 10.4 mM Ϫ1 cm Ϫ1 ) using an Agilent 8453 UV-visible spectrophotometer.…”

Section: Methodsmentioning

confidence: 99%

Characterization of the S-Denitrosation Activity of Protein Disulfide Isomerase

Sliskovic¹,

Raturi²,

Mutus

2005

Journal of Biological Chemistry

142

125

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S-Nitrosoglutathione (GSNO) denitrosation activity of recombinant human protein disulfide isomerase (PDI) has been kinetically characterized by monitoring the loss of the S-NO absorbance, using a NO electrode, and with the aid of the fluorogenic NO x probe 2,3-diaminonaphthalene. The initial rates of denitrosation as a function of [GSNO] displayed hyperbolic behavior irrespective of the method used to monitor denitrosation. The K m values estimated for GSNO were 65 ؎ 5 M and 40 ؎ 10 M for the loss in the S-NO bond and NO production (NO electrode or 2,3-diaminonaphthalene), respectively. Hemoglobin assay provided additional evidence that the final product of PDI-dependent GSNO denitrosation was NO ⅐ . A catalytic mechanism, involving a nitroxyl disulfide intermediate stabilized by imidazole (His 160 a-domain or His 589 a-domain), which after undergoing a one-electron oxidation decomposes to yield NO plus dithiyl radical, has been proposed. Evidence for the formation of thiyl/dithiyl radicals during PDI-catalyzed denitrosation was obtained with 4-((9-acridinecarbonyl)-amino)-2,2,6,6-tetramethylpiperidine-1-oxyl. Evidence has also been obtained showing that in a NO-and O 2 -rich environment, PDI can form N 2 O 3 in its hydrophobic domains. This "NO-charged PDI" can perform intra-and intermolecular S-nitrosation reactions similar to that proposed for serum albumin. Interestingly, reduced PDI was able to denitrosate S-nitrosated PDI (PDI-SNO) resulting in the release of NO. PDI-SNO, once formed, is stable at room temperature in the absence of reducing agent over the period of 2 h. It has been established that PDI is continuously secreted from cells that are net producers of NO-like endothelial cells. The present demonstration that PDI can be S-nitrosated and that PDI-SNO can be denitrosated by PDI suggests that this enzyme could be intimately involved in the transport of intracellular NO equivalents to the cell surface as well as the previous demonstration of PDI in the transfer of S-nitrosothiol-bound NO to the cytosol. Protein disulfide isomerase (PDI)1 was identified about 40 years ago (1). Although large levels of this enzyme are found in the endoplasmic reticulum, PDI is secreted from cells in which it associates electrostatically with the cell surface (2, 3). One of the most studied functions of PDI is its ability to catalyze isomerization and rearrangement of disulfide bonds in the endoplasmic reticulum, contributing to a proper folding of nascent proteins (4). Cell surface PDI was initially discovered in platelets (5), in which it plays a dual role in integrin-mediated adhesion and aggregation (6, 7), RSNO-mediated platelet inhibition, and GSNO denitrosation (8).S-Nitrosothiols (RSNOs) are known nitric oxide (NO) donors. RSNOs range in size from low molecular weight, such as cysteine-NO and homocysteine-NO, to high molecular weight nitrosated proteins, such as serum albumin-NO. They are known to prolong NO half-life (9) and to act as a NO transport system in a cellular environment (10 -12).An additional novel...

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“…For some proteins (e.g. phosphofructokinase, 3-hydroxy-3-methylglutaryl-CoA reductase, ribonuclease A, and lysozyme), oxidized thiols (disulfide state) are essential for biological function (14,15), whereas the activity of other proteins depends on maintaining critical thiols in the reduced state. Such is the case for the ryanodine receptor of the sarcoplasmic reticulum of muscle cells, which possesses sensitive sulfhydryl groups that influence the rate of Ca 2ϩ release depending upon the thiol redox status (16).…”

mentioning

confidence: 99%

Sequential Opening of Mitochondrial Ion Channels as a Function of Glutathione Redox Thiol Status

Aon

Cortassa

Maack³

et al. 2007

Journal of Biological Chemistry

182

236

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Mitochondrial membrane potential (⌬⌿ m ) depolarization contributes to cell death and electrical and contractile dysfunction in the post-ischemic heart. An imbalance between mitochondrial reactive oxygen species production and scavenging was previously implicated in the activation of an inner membrane anion channel (IMAC), distinct from the permeability transition pore (PTP), as the first response to metabolic stress in cardiomyocytes. The glutathione redox couple, GSH/GSSG, oscillated in parallel with ⌬⌿ m and the NADH/NAD ؉ redox state. Here we show that depletion of reduced glutathione is an alternative trigger of synchronized mitochondrial oscillation in cardiomyocytes and that intermediate GSH/GSSG ratios cause reversible ⌬⌿ m depolarization, although irreversible PTP activation is induced by extensive thiol oxidation. Mitochondrial dysfunction in response to diamide occurred in stages, progressing from oscillations in ⌬⌿ m to sustained depolarization, in association with depletion of GSH. Mitochondrial oscillations were abrogated by 4-chlorodiazepam, an IMAC inhibitor, whereas cyclosporin A was ineffective. In saponin-permeabilized cardiomyocytes, the thiol redox status was systematically clamped at GSH/GSSG ratios ranging from 300:1 to 20:1. At ratios of 150:1-100:1, ⌬⌿ m depolarized reversibly, and a matrix-localized fluorescent marker was retained; however, decreasing the GSH/GSSG to 50:1 irreversibly depolarized ⌬⌿ m and induced maximal rates of reactive oxygen species production, NAD(P)H oxidation, and loss of matrix constituents. Mitochondrial GSH sensitivity was altered by inhibiting either GSH uptake, the NADPH-dependent glutathione reductase, or the NADH/NADPH transhydrogenase, indicating that matrix GSH regeneration or replenishment was crucial. The results indicate that GSH/GSSG redox status governs the sequential opening of mitochondrial ion channels (IMAC before PTP) triggered by thiol oxidation in cardiomyocytes.The dual nature of oxygen as a vital electron acceptor in oxidative phosphorylation and as a dangerously reactive molecule has created pressure for the cell to evolve powerful antioxidant defenses that convert reactive oxygen species (ROS) 3 into harmless products to maintain a predominantly reduced redox environment. This depends on the following two factors: the reduction potential of the electron carriers, and the reducing capacity (i.e. the total concentration of the reduced species) of linked redox couples present in the cytoplasm or in the intraorganellar compartments (e.g. the mitochondrial matrix) of the cell. In addition to the redox couples involved in mitochondrial electron transport (the nicotinamide adenine dinucleotides NADH/NAD ϩ , and the flavins FADH 2 / FAD), the three main cellular redox pairs participating in intracellular reactions include reduced/oxidized glutathione (GSH/GSSG), thioredoxin (Trx(SH) 2 /TrxSS), and NADPH/ NADP ϩ , with the latter providing the thermodynamic driving force behind the glutathione and thioredoxin systems (1). The GSH/GSSG pool is the ...

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Reduction-Reoxidation Cycles Contribute to Catalysis of disulfide Isomerization by Protein-disulfide Isomerase

Cited by 131 publications

References 26 publications

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma

The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma

Characterization of the S-Denitrosation Activity of Protein Disulfide Isomerase

Sequential Opening of Mitochondrial Ion Channels as a Function of Glutathione Redox Thiol Status

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