Covalent modification of proteins by S -nitrosylation is an important mechanism for regulation of biochemical activity in cells. However, mechanisms of protein denitrosylation have not been well characterized. The protease caspase-3, which promotes apoptosis, is inhibited by S -nitrosylation and is denitrosylated in cells in which the cell death-promoting receptor Fas is activated. Benhar et al . (see the Perspective by Holmgren) purified a protein fraction that catalyzed denitrosylation of caspase-3 and identified thioredoxin-1 (Trx1) as the protein most likely to be responsible for the denitrosylation activity. Depletion of Trx1 caused accumulation of S -nitrosylated caspase-3 and other S -nitrosylated proteins in cultured cells, and Fas-induced denitrosylation of caspase-3 was inhibited by depleting thioredoxin reductase 2. Thus, regulated denitrosylation of target proteins by Trx1 appears to provide a key component of enzymatic regulation of caspase-3 and possibly other proteins by S- nitrosylation. M. Benhar, M. T. Forrester, D. T. Hess, J. S. Stamler, Regulated protein denitrosylation by cytosolic and mitochondrial thioredoxins. Science 320 , 1050-1054 (2008). [Abstract] [Full Text] A. Holmgren, SNO Removal. Science 320 , 1019-1020 (2008). [Summary] [Full Text]