Nucleoredoxin‐Dependent Targets and Processes in Neuronal Cells

Urbainsky, Claudia; Nölker, Rolf; Imber, Marcel; Lübken, Adrian; Mostertz, Jörg; Hochgräfe, Falko; Godoy, José R.; Hanschmann, Eva-Maria; Lillig, Christopher Horst

doi:10.1155/2018/4829872

Cited by 26 publications

(29 citation statements)

References 34 publications

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“…Nucleoredoxin (Nrx) was here identified to be deiminated in EVs only. It is an oxidoreductase of the thioredoxin family of proteins with numerous functions in the redox regulation of metabolic pathways, cellular morphology, and signal transduction (Urbainsky et al, 2018). Nrx has been shown to inhibit Wnt-beta-catenin signalling (Funato et al, 2006) and is linked to Ca 2+ -mediated mitochondrial reactive oxygen species metabolism (Rharass et al, 2014).…”

mentioning

confidence: 99%

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

Criscitiello

Kraev

Lange

2020

Molecular Immunology

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A B S T R A C TPeptidylarginine deiminases (PADs) are phylogenetically conserved calcium-dependent enzymes which posttranslationally convert arginine into citrulline in target proteins in an irreversible manner, causing functional and structural changes in target proteins. Protein deimination causes generation of neo-epitopes, affects gene regulation and also allows for protein moonlighting. Furthermore, PADs have been found to be a phylogenetically conserved regulator for extracellular vesicle (EVs) release. EVs are found in most body fluids and participate in cellular communication via transfer of cargo proteins and genetic material. In this study, post-translationally deiminated proteins in serum and serum-EVs are described for the first time in camelids, using the llama (Lama glama L. 1758) as a model animal. We report a poly-dispersed population of llama serum EVs, positive for phylogenetically conserved EV-specific markers and characterised by TEM. In serum, 103 deiminated proteins were overall identified, including key immune and metabolic mediators including complement components, immunoglobulin-based nanobodies, adiponectin and heat shock proteins. In serum, 60 deiminated proteins were identified that were not in EVs, and 25 deiminated proteins were found to be unique to EVs, with 43 shared deiminated protein hits between both serum and EVs. Deiminated histone H3, a marker of neutrophil extracellular trap formation, was also detected in llama serum. PAD homologues were identified in llama serum by Western blotting, via cross reaction with human PAD antibodies, and detected at an expected 70 kDa size. This is the first report of deiminated proteins in serum and EVs of a camelid species, highlighting a hitherto unrecognized post-translational modification in key immune and metabolic proteins in camelids, which may be translatable to and inform a range of human metabolic and inflammatory pathologies.

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mentioning

confidence: 99%

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

Criscitiello

Kraev

Lange

2020

Molecular Immunology

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“…n.a. : not analyzed (as no information on the individual domains were available).Protein nameIDActive sitepdbFunctionsloc.Interactome (number) Homo sapiens glutaredoxinsGrx1P35754CPYC1b4q, ...(de)-glutathionylationc/n24Grx2a/cQ9NS18CSYC2fls, ...Fe/S, redox sensor [52]c/m/n64 [53]Grx3.d2O76003CGFS3zywFe/S, iron metabolism [54, 55]c98Grx3.d3CGFS2yanGrx5Q86SX6CGFS2wul, ...Fe/S biogenesis [56, 57]m22TrxR1v3.d1Q16881-1CTRCcn.a.TrxR3.d1Q86VQ6CPHS2h8qcn.a.GrxCR1.d2A8MXD5FERCc9PTGES2.d1Q9H7Z7CPFC2pbjprostaglandin synthesis [58]c/l31SH3BGRL3Q9H299KSQQ1sj6cancer progression [59]c/n10 Homo sapiens thioredoxinsTrx1P10599CGPC1ert, ...electron donor, redox signaling, ... [4]c/n/o247 [60]Trx2Q99757CGPC1wh4, ...m102Grx3.d1O76003APQC2diy, ...Fe/S, iron metabolism [54, 55]csee aboveNrx.d2Q6DKJ4CPPCredox signalingc/n629 [61]Nxnl1Q96CM4CPQCn/l…”

Section: Resultsmentioning

confidence: 99%

Substrate specificity of thioredoxins and glutaredoxins – towards a functional classification

Gellert

Hossain

Berens

et al. 2019

Heliyon

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The spatio-temporal reduction and oxidation of protein thiols is an essential mechanism in signal transduction in all kingdoms of life. Thioredoxin (Trx) family proteins efficiently catalyze thiol-disulfide exchange reactions and the proteins are widely recognized for their importance in the operation of thiol switches. Trx family proteins have a broad and at the same time very distinct substrate specificity – a prerequisite for redox switching. Despite of multiple efforts, the true nature for this specificity is still under debate. Here, we comprehensively compare the classification/clustering of various redoxins from all domains of life based on their similarity in amino acid sequence, tertiary structure, and their electrostatic properties. We correlate these similarities to the existence of common interaction partners, identified in various previous studies and suggested by proteomic screenings. These analyses confirm that primary and tertiary structure similarity, and thereby all common classification systems, do not correlate to the target specificity of the proteins as thiol-disulfide oxidoreductases. Instead, a number of examples clearly demonstrate the importance of electrostatic similarity for their target specificity, independent of their belonging to the Trx or glutaredoxin subfamilies.

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“…The trapping Trx1 C35S mutant [36] was expressed and purified as His-Tag fusion protein [37]. It was immobilized and reduced with 10 mM DTT on a His-Trap column, onto which 10-20 mg proteins of HT1080 cell lysate was loaded.…”

Section: Intermediate Trapping Of Trx1 To Integrinsmentioning

confidence: 99%

Extracellular Redox Regulation of α7β Integrin-Mediated Cell Migration Is Signaled via a Dominant Thiol-Switch

et al. 2020

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While adhering to extracellular matrix (ECM) proteins, such as laminin-111, cells temporarily produce hydrogen peroxide at adhesion sites. To study the redox regulation of α7β1 integrin-mediated cell adhesion to laminin-111, a conserved cysteine pair within the α-subunit hinge region was replaced for alanines. The molecular and cellular effects were analyzed by electron and atomic force microscopy, impedance-based migration assays, flow cytometry and live cell imaging. This cysteine pair constitutes a thiol-switch, which redox-dependently governs the equilibrium between an extended and a bent integrin conformation with high and low ligand binding activity, respectively. Hydrogen peroxide oxidizes the cysteines to a disulfide bond, increases ligand binding and promotes cell migration toward laminin-111. Inversely, extracellular thioredoxin-1 reduces the disulfide, thereby decreasing laminin binding. Mutation of this cysteine pair into the non-oxidizable hinge-mutant shows molecular and cellular effects similar to the reduced wild-type integrin, but lacks redox regulation. This proves the existence of a dominant thiol-switch within the α subunit hinge of α7β1 integrin, which is sufficient to implement activity regulation by extracellular redox agents in a redox-regulatory circuit. Our data reveal a novel and physiologically relevant thiol-based regulatory mechanism of integrin-mediated cell-ECM interactions, which employs short-lived hydrogen peroxide and extracellular thioredoxin-1 as signaling mediators.

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Nucleoredoxin‐Dependent Targets and Processes in Neuronal Cells

Cited by 26 publications

References 34 publications

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

Substrate specificity of thioredoxins and glutaredoxins – towards a functional classification

Extracellular Redox Regulation of α7β Integrin-Mediated Cell Migration Is Signaled via a Dominant Thiol-Switch

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