Dysregulation of the glutaredoxin/S-glutathionylation redox axis in lung diseases

• DOI: 10.1152/ajpcell.00410.2019
• Publication Date: 2019-11-06T20:15:21Z
• Authors: Shi B. Chia; Evan A. Elko; Reem Aboushousha; Allison M. Manuel; Cheryl van de Wet...; Joseph E. Druso; Jos van der Velden; David J. Seward; Vikas Anathy; Charles G. Irvin; Ying-Wai Lam; Albert van der Vliet; Yvonne M. W. Jans...
• Keywords: Lung Diseases; 0301 basic medicine; Mice, Inbred BALB C; Glutathione; Antioxidants; 3. Good health; Mice; Oxidative Stress; 03 medical and health sciences; Animals; Humans; Amino Acid Sequence; Cysteine; Disulfides; Lung; Oxidation-Reduction; Glutaredoxins

Glutathione is a major redox buffer, reaching millimolar concentrations within cells and high micromolar concentrations in airways. While glutathione has been traditionally known as an antioxidant defense mechanism that protects the lung tissue from oxidative stress, glutathione more recently has become recognized for its ability to become covalently conjugated to reactive cysteines within proteins, a modification known as S-glutathionylation (or S-glutathiolation or protein mixed disulfide). S-glutathionylation has the potential to change the structure and function of the target protein, owing to its size (the addition of three amino acids) and charge (glutamic acid). S-glutathionylation also protects proteins from irreversible oxidation, allowing them to be enzymatically regenerated. Numerous enzymes have been identified to catalyze the glutathionylation/deglutathionylation reactions, including glutathione S-transferases and glutaredoxins. Although protein S-glutathionylation has been implicated in numerous biological processes, S-glutathionylated proteomes have largely remained unknown. In this paper, we focus on the pathways that regulate GSH homeostasis, S-glutathionylated proteins, and glutaredoxins, and we review methods required toward identification of glutathionylated proteomes. Finally, we present the latest findings on the role of glutathionylation/glutaredoxins in various lung diseases: idiopathic pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease.