Global Analysis of S-nitrosylation Sites in the Wild Type (APP) Transgenic Mouse Brain-Clues for Synaptic Pathology

Zaręba-Kozioł, Monika; Szwajda, Agnieszka; Dadlez, Michał; Wysłouch‐Cieszyńska, Aleksandra; Łałowski, Maciej

doi:10.1074/mcp.m113.036079

Cited by 40 publications

(58 citation statements)

References 145 publications

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“…S7C). Acetoacetyl-CoA thiolase has also been identified by proteomic analysis as an endogenous SNOprotein in mammals (17,18). Both endogenous and exogenous SNO-CoA-mediated S-nitrosylation of Erg10 were confirmed directly by SNO-RAC analysis of untreated extracts and extracts treated with SNO-CoA (60 μM, 10 min) ( Fig.…”

Section: Resultsmentioning

confidence: 69%

Identification of S-nitroso-CoA reductases that regulate protein S-nitrosylation

Anand

Hausladen

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Coenzyme A (CoA) mediates thiol-based acyl-group transfer (acetylation and palmitoylation). However, a role for CoA in the thiol-based transfer of NO groups (S-nitrosylation) has not been considered. Here we describe protein S-nitrosylation in yeast (heretofore unknown) that is mediated by S-nitroso-CoA (SNO-CoA). We identify a specific SNO-CoA reductase encoded by the alcohol dehydrogenase 6 (ADH6) gene and show that deletion of ADH6 increases cellular S-nitrosylation and alters CoA metabolism. Further, we report that Adh6, acting as a selective SNO-CoA reductase, protects acetoacetyl-CoA thiolase from inhibitory S-nitrosylation and thereby affects sterol biosynthesis. Thus, Adh6-regulated, SNO-CoA-mediated protein S-nitrosylation provides a regulatory mechanism paralleling protein acetylation. We also find that SNO-CoA reductases are present from bacteria to mammals, and we identify aldo-keto reductase 1A1 as the mammalian functional analog of Adh6. Our studies reveal a novel functional class of enzymes that regulate protein S-nitrosylation from yeast to mammals and suggest that SNO-CoA-mediated S-nitrosylation may subserve metabolic regulation.

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Section: Resultsmentioning

confidence: 69%

Identification of S-nitroso-CoA reductases that regulate protein S-nitrosylation

Anand

Hausladen

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…4b) indicating the potential alteration of energy production and utilization in AD mouse liver tissue. This is consistent with the following: (1) dysregulated metabolic processes such as β-oxidation, pyruvate metabolism, and glucose regulation in AD liver [37]; (2) alterations in carbohydrate metabolism, lipid metabolism and amino acid metabolism [28]; and (3) differential S-nitrosylation of proteins involved in energy metabolism and oxidative phosphorylation [14]. Further examination of redox-sensitive cysteine residues in Uniprot [42] was used to help with biological interpretation of changes in cysteine status.…”

Section: Application Of Oxcysdml To An Ad Mouse Modelmentioning

confidence: 85%

“…Our previous studies of peripheral organs and cells in an AD mouse model indicated dysregulated metabolic pathways in liver tissue [28,37] and elevated oxidative stress in T cells [45]. Although oxidative stress-induced cysteine PTMs (e.g., S-nitrosylation, S-glutathionylation) in AD have been reported, most of these studies were focused on brain tissue and used gel-based methods [13,14,17,[46][47][48]. The role of peripheral organs involved in AD is still not clear.…”

Section: Application Of Oxcysdml To An Ad Mouse Modelmentioning

confidence: 95%

“…It has been widely accepted that oxidative stress plays an important role in AD pathogenesis [11]. Proteomic methods coupled with 2D gel electrophoresis and affinity enrichment have identified the brain proteins that are significantly S-glutathionylated [12] or S-nitrosylated [13][14][15] in AD patients or transgenic mouse models relative to controls. These modifications are likely due to elevated oxidative stress and are involved in various cellular pathways, such as glycolysis, calcium homeostasis, and vesicle transport [12,14,15].…”

Section: Introductionmentioning

confidence: 99%

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A simple isotopic labeling method to study cysteine oxidation in Alzheimer’s disease: oxidized cysteine-selective dimethylation (OxcysDML)

Robinson

2016

Anal Bioanal Chem

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Cysteine is widely involved in redox signaling pathways through a number of reversible and irreversible modifications. Reversible modifications (e.g., S-glutathionylation, S-nitrosylation, disulfide bonds, and sulfenic acid) are used to protect proteins from oxidative attack and maintain cellular homeostasis, while irreversible oxidations (e.g., sulfinic acid and sulfonic acid) serve as hallmarks of oxidative stress. Proteomic analysis of cysteine-enriched peptides coupled with reduction of oxidized thiols can be used to measure the oxidation states of cysteine, which is helpful for elucidating the role that oxidative stress plays in biology and disease. As an extension of our previously reported cysDML method, we have developed oxidized cysteine-selective dimethylation (OxcysDML), to investigate the site-specific total oxidation of cysteine residues in biologically relevant samples. OxcysDML employs (1) blocking of free thiols by a cysteine-reactive reagent, (2) enrichment of peptides containing reversibly oxidized cysteine by a solid phase resin, and (3) isotopic labeling of peptide amino groups to quantify cysteine modifications arising from different biological conditions. On-resin enrichment and labeling minimizes sample handing time and improves efficiency in comparison with other redox proteomic methods. OxcysDML is also inexpensive and flexible, as it can accommodate the exploration of various cysteine modifications. Here, we applied the method to liver tissues from a late-stage Alzheimer's disease (AD) mouse model and wild-type (WT) controls. Because we have previously characterized this proteome using the cysDML approach, we are able here to probe deeper into the redox status of cysteine in AD. OxcysDML identified 1129 cysteine sites (from 527 proteins), among which 828 cysteine sites underwent oxidative modifications. Nineteen oxidized cysteine sites had significant alteration levels in AD and represent proteins involved in metabolic processes. Overall, we have demonstrated OxcysDML as a simple, rapid, robust, and inexpensive redox proteomic approach that is useful for gaining deeper insight into the proteome of AD.

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“…Interestingly, both S100A9 and iNOS are enriched in macrophage-rich regions in the Alzheimer’s disease (AD) brain, and depletion of either provides significant clinical benefits in animal models of AD (Ha et al, 2010; Nathan et al, 2005). Recent studies of differential protein S -nitrosylation revealed 45 AD-associated SNO-proteins in humans and 33 in mouse models of AD (Zahid et al, 2014; Zareba-Koziol et al, 2014). Interestingly, 6 human and 6 mouse AD-associated SNO-proteins contain the I/L-X-C-X 2 -D/E motif.…”

Section: Discussionmentioning

confidence: 99%

Target-Selective Protein S-Nitrosylation by Sequence Motif Recognition

Jia

Arif

Terenzi

et al. 2014

Cell

152

147

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SUMMARY S-nitrosylation is a ubiquitous protein modification emerging as a principal mechanism of nitric oxide (NO)-mediated signal transduction and cell function. S-nitrosylases can use NO synthase (NOS)-derived NO to modify selected cysteines in target proteins. Despite proteomic identification of more than a thousand S-nitrosylated proteins, very few S-nitrosylases have been identified. Moreover, mechanisms underlying site-selective S-nitrosylation and the potential role of specific sequence motifs remain largely unknown. Here, we describe a stimulus-inducible, heterotrimeric S-nitrosylase complex consisting of inducible NOS (iNOS), S100A8, and S100A9. S100A9 exhibits transnitrosylase activity, shuttling NO from iNOS to the target protein, whereas S100A8 and S100A9 coordinately direct site selection. A family of proteins S-nitrosylated by the iNOS-S100A8/A9 complex were revealed by proteomic analysis, and validated as targets. A conserved I/L-X-C-X2-D/E motif was necessary and sufficient for iNOS- S100A8/A9-mediated S-nitrosylation. These results reveal an elusive parallel between protein S-nitrosylation and phosphorylation, namely, stimulus-dependent post-translational modification of selected targets by primary sequence motif recognition.

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Global Analysis of S-nitrosylation Sites in the Wild Type (APP) Transgenic Mouse Brain-Clues for Synaptic Pathology

Cited by 40 publications

References 145 publications

Identification of S-nitroso-CoA reductases that regulate protein S-nitrosylation

Identification of S-nitroso-CoA reductases that regulate protein S-nitrosylation

A simple isotopic labeling method to study cysteine oxidation in Alzheimer’s disease: oxidized cysteine-selective dimethylation (OxcysDML)

Target-Selective Protein S-Nitrosylation by Sequence Motif Recognition

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