Thioredoxin‐related protein of 14 kDa as a modulator of redox signalling pathways

Abstract

Thioredoxin-related protein of 14 kDa (TRP14; also named TXNDC17 for thioredoxin domain-containing protein 17) is a highly conserved and ubiquitously expressed oxidoreductase. It is expressed in parallel with thioredoxin 1 (Trx1, TXN; TXN1), an efficient substrate for the mammalian cytosolic selenoprotein thioredoxin reductase 1 (TrxR1; TXNRD1). However, TRP14, in sharp contrast to Trx1, cannot support the activities of ribonucleotide reductase, peroxiredoxins or methionine sulfoxide reductases, thus is unable to directly support cell proliferation or antioxidant defence through these pathways. However, TRP14 has been shown to efficiently reduce l-cystine, which thereby indirectly supports glutathione synthesis. TRP14 can also suppress NF-κB signalling, is functionally linked to STAT3 signalling, and can directly reactivate oxidized protein-tyrosine phosphatase PTP1B. Furthermore, TRP14 can efficiently reduce persulfidated or nitrosylated cysteine residues in many proteins, thereby having the capacity to modulate signalling through hydrogen sulfide or NO. Additional bioinformatics analyses and observations suggest further roles for TRP14; therefore, further studies of its functions are warranted. Collectively, the results available suggest that TRP14 is a member of the thioredoxin system dedicated to the control of cellular redox signalling pathways.

<p>Sodium Butyrate Selectively Kills Cancer Cells and Inhibits Migration in Colorectal Cancer by Targeting Thioredoxin-1</p>

“…40 As an auxiliary factor of intracellular antioxidant and reductant, Trx-1 is widely involved in several functions of cells including protein disulfifide reduction, oxidative stress regulation and regulation of transcription factor. [41][42][43] Our previous study has shown that Trx-1 has an important role in CRC and the elevation of Trx-1 promoted cancer invasion and metastasis by promoting the EMT in CRC. 25 EMT is an intricate process during which cells lose epithelial characteristics, gain mesenchymal properties and increased motility, and is associated with cancer invasion and metastasis in CRC.…”

Sulfur Metabolism Under Stress

“…Another important Cys modification in cells is Cyspersulfidation (Cys-SSH) (11,51). Protein-Cys-persulfides are readily reduced by cellular redoxins (25,26,29,135), yielding a Cys-thiol and H 2 S. This modification is therefore a likely regulator of enzyme activity and signaling pathways, although the extent of this use of protein-persulfidation remains largely undefined (60). Liberation of H 2 S as a result of regulation of specific individual proteins is unlikely to be substantial; however, some studies suggest that protein persulfides might be more abundant than expected, in which case their redoxin-catalyzed conversion to thiols could generate large amounts of H 2 S in cells or subcellular compartments.…”

Thioredoxins: Emerging Players in the Regulation of Protein S-Nitrosation in Plants

“…In summary, NO and the TRX system show a complex interplay within the redox regulation of mammalian cells, where TRXs play an active role in attenuating NO signaling and responses to nitrosative stress, whereas NO reciprocally modulates the redox activity of TRX and TRXRs. Furthermore, TRX-related protein of 14 kDa (TRP14), a highly conserved and ubiquitously expressed oxidoreductase that efficiently reduces L-cystine, was recently reported also to reduce S-nitrosated or persulfidated protein cysteines, thereby potentially modulating both NO and H 2 S signaling [73].…”