Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine 69

Abstract

Thioredoxin 1 (Trx) is a known redox regulator that is implicated in the redox control of cell growth and apoptosis inhibition. Here we show that Trx is essential for maintaining the content of S-nitrosylated molecules in endothelial cells. Trx itself is S-nitrosylated at cysteine 69 under basal conditions, and this S-nitrosylation is required for scavenging reactive oxygen species and for preserving the redox regulatory activity of Trx. S-nitrosylation of Trx also contributes to the anti-apoptotic function of Trx. Thus, Trx can exert its complete redox regulatory and anti-apoptotic functions in endothelial cells only when cysteine 69 is S-nitrosylated.

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

“…Intriguingly, in addition to Grx itself, Trx and PDI are targets for S-glutathionylation [109,110]. 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].…”

“…S-nitrosylation resulted in decreased activity of Grx [106]. Furthermore, Trx [107,108] and protein disulfide isomerase (PDI) (see below) are also targets for S-nitrosylation. Intriguingly, in addition to Grx itself, Trx and PDI are targets for S-glutathionylation [109,110].…”

“…Trx is subject to S-nitrosylation at multiple sites. 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.…”

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

“…Among the signaling proteins (and their critical cysteines) that have been well characterized are the PTPs, PTP1B (cys 215 ) (26,27,(34)(35)(36), low molecular weight PTP (cys12,17) (37-39) and Srchomology 2 domain-containing PTP (SHP-2) (40), the small G protein, Ras (cys 118 ) (41)(42)(43)(44), the large G proteins, G i (cys 267 ) and G o (cys 326 ) (45) and the lipid phosphatase, phosphatase and tensin homolog deleted on chromosome 10 (PTEN). In addition, as mentioned above, in its reduced form Trx binds and inhibits ASK1 and possibly other signaling proteins as well (46)(47)(48)(49)(50)(51)(52)(53). When oxidized by formation of a disulfide between the two cysteines in its active site, Trx dissociates from ASK1, allowing it to become activated (46)(47)(48)(49)(50)(51)(52)(53) (Figure 1).…”

“…In addition, as mentioned above, in its reduced form Trx binds and inhibits ASK1 and possibly other signaling proteins as well (46)(47)(48)(49)(50)(51)(52)(53). When oxidized by formation of a disulfide between the two cysteines in its active site, Trx dissociates from ASK1, allowing it to become activated (46)(47)(48)(49)(50)(51)(52)(53) (Figure 1). Also, GSTΠ inhibits c-Jun-N-terminal kinase (JNK) but dissociates and allows JNK activation when its critical active site cysteine is oxidized (54)(55)(56).…”