S-Glutathionylation: From Molecular Mechanisms to Health Outcomes

Redox homeostasis governs a number of critical cellular processes. In turn, imbalances in pathways that control oxidative and reductive conditions have been linked to a number of human disease pathologies, particularly those associated with aging. Reduced glutathione is the most prevalent biological thiol and plays a crucial role in maintaining a reduced intracellular environment. Exposure to reactive oxygen or nitrogen species is causatively linked to the disease pathologies associated with redox imbalance. In particular, reactive oxygen species can differentially oxidize certain cysteine residues in target proteins and the reversible process of S-glutathionylation may mitigate or mediate the damage. This post-translational modification adds a tripeptide and a net negative charge that can lead to distinct structural and functional changes in the target protein. Because it is reversible, S-glutathionylation has the potential to act as a biological switch and to be integral in a number of critical oxidative signaling events. The present review provides a comprehensive account of how the S-glutathionylation cycle influences protein structure/function and cellular regulatory events, and how these may impact on human diseases. By understanding the components of this cycle, there should be opportunities to intervene in stress- and aging-related pathologies, perhaps through prevention and diagnostic and therapeutic platforms. Antioxid. Redox Signal. 15, 233–270. I. Introduction A. Glutathione homeostasis B. Proximal donors for S-glutathionylation reactions II. Detection of S-Glutathionylation A. Antibody detection of S-glutathionylation B. Analytical detection and quantification of P-SSG III. Enzymes That Catalyze the S-Glutathionylation Cycle A. Proteins with S-glutathionylase activity 1. Glutathione S-transferases 2. Gamma-glutamyl transpeptidase 3. Grx1 and Grx2 B. Proteins with deglutathionylase activity IV. Redox Regulation of Kinase Signaling Pathways A. S-glutathionylation and modulation of mitogenic signaling 1. Ras-MEK-ERK pathway 2. Protein tyrosine phosphatases 3. Protein kinase A B. Phosphatidylinositol 3-kinase-Akt-p53 pathway C. I kappa B kinase-nuclear factor kappa B pathway D. JNK-c-Jun pathway V. S-Glutathionylation and Modulation of Survival/Apoptosis A. S-glutathionylation of death receptors B. S-glutathionylation of caspases VI. Redox Regulation of Calcium-Dependent Proteins A. Protein kinase C B. Sarco/ER calcium ATPase C. Nitric oxide synthase VII. S-Glutathionylation and Ubiquitin-Proteasome Pathway VIII. S-Glutathionylation and Unfolded Protein Response A. Signaling pathways in the unfolded protein response B. Protein disulfide isomerase IX. Redox Regulation of Cell Migration and Mobilization A. S-glutathionylation of cytoskeletal proteins B. Redox regulation of bone marrow mobilization X. Cancer and Redox Homeostasis A. Energy metabolism B. S-glutathionylation and tumor metastasis C. S100 proteins in cancer and leukocyte migration 1. S100B 2. S100A8 and S100A9 XI. Redox Dysregulation in Pathophysiology A. Liver injury B. Diabetes mellitus C. Cardiovascular disease D. Traumatic brain injury XII. Neurological Diseases and Redox Pathways A. Parkinson's disease B. Alzheimer's disease C. Huntington's disease D. Friedreich's ataxia E. Amylotrophic lateral sclerosis XIII. Conclusions