Protein disulfide isomerases: Redox connections in and out of the endoplasmic reticulum

Moretti, Ana Iochabel Soares; Laurindo, Francisco Rafael Martins

doi:10.1016/j.abb.2016.11.007

Cited by 92 publications

(90 citation statements)

References 189 publications

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“…This inference may be premature and should be confirmed by additional experimental support. In fact, further studies will be required to clarify the roles of individual PDI domains in the physiological functions of the enzyme (63). In this work, we used diverse methodologies that, taken together, indicate that PDI domains a and aЈ behave similarly with regard to peroxynitrite-mediated oxidation, and all of our data are consistent with the mechanism proposed in Fig.…”

Section: Pdi Oxidation By Peroxynitritesupporting

confidence: 78%

“…6A). Next, the unmodified peptide of untreated PDI that decreased most (74%) to produce the corresponding nitrated peptide in treated PDI was the peptide containing Tyr 63 (ALAPEYAK) (Fig. 6A).…”

Section: Pdi Oxidation By Peroxynitritementioning

confidence: 99%

“…5D) (43,51). Accordingly, MS and MS/MS analyses of the formed oxidation products from PDI (10 M) treated with peroxynitrite (200 M) showed that PDI was nitrated at several residues, particularly at Tyr 63 (Fig. 6 and Table S3).…”

mentioning

confidence: 93%

“…Although low-level PDI oxidation in the ER might potentially favor PDI chaperone activity or substrate thiol oxidation to improve folding, PDI oxidation associates mainly with impairment of PDI isomerase activity (62). PDI may also translocate to the cytosol, although this is still controversial (63). In both ER and cytosol, PDI will face strong kinetic competition with abundant proteins, such as peroxiredoxins (31, 56 -58), to react with peroxynitrite.…”

mentioning

confidence: 99%

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Peroxynitrite preferentially oxidizes the dithiol redox motifs of protein-disulfide isomerase

Peixoto

Geyer

Iqbal

et al. 2018

Journal of Biological Chemistry

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Protein-disulfide isomerase (PDI) is a ubiquitous dithiol-disulfide oxidoreductase that performs an array of cellular functions, such as cellular signaling and responses to cell-damaging events. PDI can become dysfunctional by post-translational modifications, including those promoted by biological oxidants, and its dysfunction has been associated with several diseases in which oxidative stress plays a role. Because the kinetics and products of the reaction of these oxidants with PDI remain incompletely characterized, we investigated the reaction of PDI with the biological oxidant peroxynitrite. First, by determining the rate constant of the oxidation of PDI's redox-active Cys residues (Cys and Cys) by hydrogen peroxide ( = 17.3 ± 1.3 m s at pH 7.4 and 25 °C), we established that the measured decay of the intrinsic PDI fluorescence is appropriate for kinetic studies. The reaction of these PDI residues with peroxynitrite was considerably faster ( = (6.9 ± 0.2) × 10 m s), and both Cys residues were kinetically indistinguishable. Limited proteolysis, kinetic simulations, and MS analyses confirmed that peroxynitrite preferentially oxidizes the redox-active Cys residues of PDI to the corresponding sulfenic acids, which reacted with the resolving thiols at the active sites to produce disulfides ( Cys-Cys and Cys-Cys). A fraction of peroxynitrite, however, decayed to radicals that hydroxylated and nitrated other active-site residues (Trp, Trp, and Tyr). Excess peroxynitrite promoted further PDI oxidation, nitration, inactivation, and covalent oligomerization. We conclude that these PDI modifications may contribute to the pathogenic mechanism of several diseases associated with dysfunctional PDI.

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Section: Pdi Oxidation By Peroxynitritesupporting

confidence: 78%

Section: Pdi Oxidation By Peroxynitritementioning

confidence: 99%

mentioning

confidence: 93%

mentioning

confidence: 99%

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Peroxynitrite preferentially oxidizes the dithiol redox motifs of protein-disulfide isomerase

Peixoto

Geyer

Iqbal

et al. 2018

Journal of Biological Chemistry

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“…Furthermore, it has been proposed that the absence of PDIA1 and probably of other PDIs from plasma in the intact circulatory system is a mechanism to suppress thrombus formation and maintain vascular patency in the absence of vascular injury [133]. PDIA1 secretion under acute shear stress in endothelial cells is able to oxidize α5-integrin [131], although secreted PDIA1 most often acts as a thiol reductase [134]. PDIA1 interaction with Nox NADPH oxidases may provide an additional redox connection [135].…”

Section: The Plasma Thiol-proteomementioning

confidence: 99%

Proteína dissulfeto isomerase plasmática: detecção e correlação com assinaturas proteômicas ligadas a distintos fenótipos endoteliais em indivíduos saudáveis

Oliveira¹

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Pharmacologic Targeting of PDIA1 Inhibits NLRP3 Inflammasome Assembly and Activation

Rosarda,

Stanton,

Chen

et al. 2023

Israel Journal of Chemistry

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The NLRP3 inflammasome is a cytosolic protein complex that regulates innate immune signaling in response to diverse pathogenic insults through the proteolytic processing and secretion of pro‐inflammatory cytokines such as IL‐1β. Hyperactivation of NLRP3 inflammasome signaling is implicated in the onset and pathogenesis of numerous diseases, motivating the discovery of new strategies to suppress NLRP3 inflammasome activity. We sought to define the potential for the proteostasis regulator AA147 to inhibit the assembly and activation of the NLRP3 inflammasome. AA147 is a pro‐drug that is metabolically converted to a reactive metabolite at the endoplasmic reticulum (ER) membrane to covalently modify ER‐localized proteins such as protein disulfide isomerases (PDIs). We show that AA147 inhibits NLRP3 inflammasome activity in monocytes and monocyte‐derived macrophages through a mechanism involving impaired assembly of the active inflammasome complex. This inhibition is mediated through AA147‐dependent covalent modification of PDIA1. Genetic depletion or treatment with other highly selective PDIA1 inhibitors similarly blocks NLRP3 inflammasome assembly and activation. Our results identify PDIA1 as a potential therapeutic target to mitigate NLRP3 inflammasome‐mediated pro‐inflammatory signaling implicated in etiologically diverse diseases.

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Protein disulfide isomerases: Redox connections in and out of the endoplasmic reticulum

Cited by 92 publications

References 189 publications

Peroxynitrite preferentially oxidizes the dithiol redox motifs of protein-disulfide isomerase

Peroxynitrite preferentially oxidizes the dithiol redox motifs of protein-disulfide isomerase

Proteína dissulfeto isomerase plasmática: detecção e correlação com assinaturas proteômicas ligadas a distintos fenótipos endoteliais em indivíduos saudáveis

Pharmacologic Targeting of PDIA1 Inhibits NLRP3 Inflammasome Assembly and Activation

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