Oxidation-reduction status (redox) is an important regulator of various metabolic functions of the cell. Perturbations in the redox status of cells by external or internal stimuli elicit distinct responses, resulting in alteration of cell function. Glutathione and thioredoxin are two major reducing systems of the eukaryotic cell that maintain redox balance, as well as interact with various transducer and effector molecules to bring about specific responses. However, these two systems differ greatly in their functions and responses to various types of stress. Oxidative stress profoundly impacts them both by direct or indirect oxidation of sulfhydryl groups. Glutathione is a small tripeptide with a single cysteine residue that undergoes oxidation-reduction (1). Thioredoxin (Trx) is an approximately 12-kD protein that contains five cysteine residues (two catalytic and three structural). These cysteines undergo oxidation-reduction reactions in response to oxidants or reductants in the environment (2). To date, the glutathione and thioredoxin systems were considered parallel redox systems, although their functions were distinct and divergent. However, an interesting study appearing in this issue of PNAS provides a potential basis for interaction of these two redox systems in response to oxidative stress. This study by Casagrande and colleagues (3) presents data that not only demonstrates a potential link between these two redox systems, but also delineates the mechanism by which glutathionylation of Trx can inactivate this multifunctional redox protein. This study opens an area for investigation of possible in vivo interactions between these two redox systems, and the functional significance of such interactions during oxidative stress. Thioredoxin is a low molecular weight protein with cytoplasmic, membrane, extracellular, and mitochondrial distribution (2). This protein was originally identified in Escherichia coli as a hydrogen donor for ribonucleotide reductase, the essential enzyme providing deoxyribonucleotide for DNA replication (2). The Trx system includes Trx and thioredoxin reductase (TR), uses NADPH as a source of reducing equivalents, and is an efficient protein disulfide reductase. Thioredoxin peroxidase (peroxiredoxin; Prx) is a 25-kD peroxidase, initially identified in yeast, that reduces H2O2 to water and molecular oxygen with the use of electrons provided by thioredoxin (4). There are at least one mitochondrial and two cytoplasmic forms of thioredoxin peroxidase (4). Thioredoxin, thioredoxin reductase, and thioredoxin peroxidase constitute the thioredoxin system, which is very similar to the glutathione system, but with a number of distinct and different functions. The active site of Trx, Trp-Cys-Gly-Pro-Cys, is highly conserved across species (2). Besides the active site cysteines, thioredoxin has three other structural cysteines. Thioredoxin previously was shown to dimerize under oxidative stress. When this dimerization occurs, Cys-72 forms the disulfide bridge (5). Casagrande and colleagues (3) have shown that Cys-72 also is the site where glutathionylation occurs, resulting in inactivation of the protein. Thioredoxin expression increases during a variety of oxidative stress conditions. The expression of thioredoxin and of TR were increased in lungs of newborn infant baboons in response to elevated oxygen tension experienced as a result of premature birth (6). In addition, the expression of thioredoxin peroxidase also was increased in response to increased oxygen concentration in lungs of such premature newborn baboons (7). Thioredoxin protein expression increases in response to retinal ischemia-reperfusion (8), and in response to phorbol ester, interferon (9), retinoids …