Glutathione: new roles in redox signaling for an old antioxidant

Abstract

The physiological roles played by the tripeptide glutathione have greatly advanced over the past decades superimposing the research on free radicals, oxidative stress and, more recently, redox signaling. In particular, GSH is involved in nutrient metabolism, antioxidant defense, and regulation of cellular metabolic functions ranging from gene expression, DNA and protein synthesis to signal transduction, cell proliferation and apoptosis. This review will be focused on the role of GSH in cell signaling by analysing the more recent advancements about its capability to modulate nitroxidative stress, autophagy, and viral infection.

Keywords: autophagy; nitric oxide; reactive oxygen species; redox signal; viral infection.

FIGURE 1

Role of GSH in modulating cell response to NO. In cells of neuronal or muscle origin NO is produced by neuronal nitric oxide synthase (nNOS). Intracellular GSH is a crucial factor in modulating NO reactivity, as it functions as an efficient NO buffer. When GSH levels decline, NO availability is increased and may trigger DNA damage as well as protein oxidation, in terms of S-nitrosylation of cyteines and formation of 3-nitrotyrosine on protein residues. This leads to induction of caspase-independent apotosis via the activation of the apoptosis inducing factor (AIF). Concomitantly, p53 is activated and binds to consensus sequence of PGC-1a promoter increasing its expression. PGC-1a in turn co-activates the NEFL2-dependent expression of antioxidant genes, thus limiting oxidative damage and cell death.

FIGURE 2

Role of GSH in the modulation of ATG. Lack of nutrients leads to increased reactive oxygen species (ROS) production concomitant to intracellular GSH efflux through the cell membrane. These events result in thiol redox unbalance leading to activation of crucial proteins involved in ATG induction and execution. Under nutrient restriction, the phoshorylative signaling cascade governed by p38^MAPK favors glucose uptake leading to the increase of NADPH production via the enhancement of pentose phosphate pathway (PPP). NADPH in turn contributes to buffer higher ROS-mediated oxidative damage.

FIGURE 3

Modulation of intracellular GSH level during Sendai and Influenza virus infection. In the early phase of infection, host cell membrane perturbation causes decrease of intracellular pH and GSH efflux allowing virus cycle start. In the late phase of infection, GSH is also engaged in forming mixed disulfides with viral proteins. GSH intracellular levels are further decreased as its component cysteine is incorporated into viral proteins.