Redox Regulation Glutaredoxin-1 and Protein -Glutathionylation.

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 -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 -glutathionylation and irreversibly modify cysteine residues, disrupting redox signaling. 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 -transferase (GST), peroxiredoxins, and occasionally glutaredoxins can also catalyze protein -glutathionylation, thus promoting a dynamic redox environment. The latest studies of glutaredoxin-1 () transgenic or knockout mice demonstrate important distinct roles of in a variety of pathologies. Endogenous is essential to maintain normal hepatic lipid homeostasis and prevent fatty liver disease. Further, deletion of 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. Although -glutathionylation modifies many proteins, these studies suggest that -glutathionylation and Glrx regulate specific pathways , and they implicate Glrx as a potential novel therapeutic target to treat diverse disease conditions. . 32, 677-700.