Thioredoxin is required for S-nitrosation of procaspase-3 and the inhibition of apoptosis in Jurkat cells

Redox-based regulation of signal transduction: Principles, pitfalls, and promises

“…S-glutathionylation of Trx at cysteine 72, abolished the disulfide reductase activity of Trx [109], whereas S-nitrosylation of cysteine 63 was reported to increase Trx activity [107]. S-nitrosylation of cysteine 72 has been recently implicated in transnitrosation of caspases, but did not seem to affect Trx activity [111,112]. Interestingly Trx may also impact S-nitrosothiol homeostasis via its ability to cleave GSNO and protein SNO [60,113].…”

“…S-nitrosylation of cysteine 69 that lies outside the active site occurs under basal conditions, facilitates oxidoreductase activity, and is associated with protection of apoptosis [107]. Additional reports that S-nitrosylated Trx specifically transnitrosylates pro-caspase 3 [111,112] underscore the functional importance of Trx in protection against apoptosis. In contrast, S-nitrosylation of active site site cysteines (32 and/ or 35) promotes disruption of ASK1 and is associated with enhanced apoptosis [108].…”

“…In response to a proapoptotic stimulus, such as Fas ligand of tumor necrosis factor-α (TNFα), caspase denitrosylation occurs in association with activation and subsequent execution of the apoptotic pathway [53,133] (Figure 2, box 1). Intriguingly, it has been suggested that Trx (Cys 73-SNO) may exert an antiapoptotic effect by trans-nitrosylation of pro-caspase 3 [111,112]. In addition, H 2 O 2 has been shown to inhibit the activation of caspases [134].…”

Crystal structure of human thioredoxin revealing an unraveled helix and exposed S‐nitrosation site

“…Both tagged and untagged proteins are readily S-nitrosated at Cys 73 and this modification appears to be crucial for SNO exchange with caspase-3. 8,9 However, the SNO modification is readily lost in the untagged protein through Cys 73-Cys 73 0 disulfide bond formation. Cys 62 SNO has yet to be detected in the tagged protein, perhaps due to a change in Cys 62 reactivity, a change in Cys 62-Cys 69 disulfide bond propensity, or to the difficulty in detecting buried SNO moieties by mass spectrometry or chemical approaches such as the biotin switch.…”

“…Each of these has been implicated in S-nitrosation activities (also called S-nitrosylation), particularly with respect to regulation of apoptosis. [7][8][9][10][11][12][13][14] S-nitrosation/nitrosylation is the addition of NO to a cysteine residue, a redox reaction requiring one electron oxidation, and numerous proteins have been suggested to be regulated in this manner. 15 Removal of the nitroso group in target proteins, or transfer of the group to other proteins, is likely to involve hTrx1 in human cells.…”