Dataset Information

Redox Regulation via Glutaredoxin-1 and Protein S-Glutathionylation.

ABSTRACT: Significance: Over the past several years, oxidative post-translational modifications of protein cysteines have been recognized for their critical roles in physiology and pathophysiology. Cells have harnessed thiol modifications involving both oxidative and reductive steps for signaling and protein processing. One of these stages requires oxidation of cysteine to sulfenic acid, followed by two reduction reactions. First, glutathione (reduced glutathione [GSH]) forms a S-glutathionylated protein, and second, enzymatic or chemical reduction removes the modification. Under physiological conditions, these steps confer redox signaling and protect cysteines from irreversible oxidation. However, oxidative stress can overwhelm protein S-glutathionylation and irreversibly modify cysteine residues, disrupting redox signaling. Critical Issues: Glutaredoxins mainly catalyze the removal of protein-bound GSH and help maintain protein thiols in a highly reduced state without exerting direct antioxidant properties. Conversely, glutathione S-transferase (GST), peroxiredoxins, and occasionally glutaredoxins can also catalyze protein S-glutathionylation, thus promoting a dynamic redox environment. Recent Advances: The latest studies of glutaredoxin-1 (Glrx) transgenic or knockout mice demonstrate important distinct roles of Glrx in a variety of pathologies. Endogenous Glrx is essential to maintain normal hepatic lipid homeostasis and prevent fatty liver disease. Further, in vivo deletion of Glrx protects lungs from inflammation and bacterial pneumonia-induced damage, attenuates angiotensin II-induced cardiovascular hypertrophy, and improves ischemic limb vascularization. Meanwhile, exogenous Glrx administration can reverse pathological lung fibrosis. Future Directions: Although S-glutathionylation modifies many proteins, these studies suggest that S-glutathionylation and Glrx regulate specific pathways in vivo, and they implicate Glrx as a potential novel therapeutic target to treat diverse disease conditions. Antioxid. Redox Signal. 32, 677-700.

SUBMITTER: Matsui R

PROVIDER: S-EPMC7047114 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Redox Regulation via Glutaredoxin-1 and Protein S-Glutathionylation.

Matsui Reiko R Ferran Beatriz B Oh Albin A Croteau Dominique D Shao Di D Han Jingyan J Pimentel David Richard DR Bachschmid Markus Michael MM

Antioxidants & redox signaling 20200123 10

Significance: Over the past several years, oxidative post-translational modifications of protein cysteines have been recognized for their critical roles in physiology and pathophysiology. Cells have harnessed thiol modifications involving both oxidative and reductive steps for signaling and protein processing. One of these stages requires oxidation of cysteine to sulfenic acid, followed by two reduction reactions. First, glutathione (reduced glutathione [GSH]) forms a S-glut ...[more]

PMID: 31813265

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Project description:Engineered nanoparticles (ENPs) are increasingly utilized for commercial and medical applications; thus, understanding their potential adverse effects is an important societal issue. Herein, we investigated protein S-glutathionylation (SSG) as an underlying regulatory mechanism by which ENPs may alter macrophage innate immune functions, using a quantitative redox proteomics approach for site-specific measurement of SSG modifications. Three high-volume production ENPs (SiO2, Fe3O4, and CoO) were selected as representatives which induce low, moderate, and high propensity, respectively, to stimulate cellular reactive oxygen species (ROS) and disrupt macrophage function. The SSG modifications identified highlighted a broad set of redox sensitive proteins and specific Cys residues which correlated well with the overall level of cellular redox stress and impairment of macrophage phagocytic function (CoO > Fe3O4 ? SiO2). Moreover, our data revealed pathway-specific differences in susceptibility to SSG between ENPs which induce moderate versus high levels of ROS. Pathways regulating protein translation and protein stability indicative of ER stress responses and proteins involved in phagocytosis were among the most sensitive to SSG in response to ENPs that induce subcytoxic levels of redox stress. At higher levels of redox stress, the pattern of SSG modifications displayed reduced specificity and a broader set pathways involving classical stress responses and mitochondrial energetics (e.g., glycolysis) associated with apoptotic mechanisms. An important role for SSG in regulation of macrophage innate immune function was also confirmed by RNA silencing of glutaredoxin, a major enzyme which reverses SSG modifications. Our results provide unique insights into the protein signatures and pathways that serve as ROS sensors and may facilitate cellular adaption to ENPs, versus intracellular targets of ENP-induced oxidative stress that are linked to irreversible cell outcomes.

Dataset Information

Redox Regulation via Glutaredoxin-1 and Protein S-Glutathionylation.

Publications

Redox Regulation <i>via</i> Glutaredoxin-1 and Protein <i>S</i>-Glutathionylation.

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