Thioredoxin-related protein 14, a new member of the thioredoxin family with disulfide reductase activity: Implication in the redox regulation of TNF-α signaling

Woojin Jeong, Yuyeon Jung, Hojin Kim, Sun Joo Park, Sue Goo Rhee

Research output: Contribution to journalReview articlepeer-review

40 Scopus citations

Abstract

Thioredoxin-related protein 14 (TRP14) is a novel 14-kDa disulfide reductase with two active site Cys residues in its WCPDC motif, which is comparable to the WCGPC motif of thioredoxin (Trx). Although the active site cysteine of TRP14 is sufficiently nucleophilic, its redox potential is similar to that of Trx1, and it receives the electrons from Trx reductase 1 (TrxR1) as does Trx1. TRP14 does not target the same substrate as Trx1, suggesting that TRP14 and Trx1 might act on distinct substrate proteins. Comparison of the crystal structures of TRP14 and Trx1 reveals distinct surface structures in the vicinity of their active sites. Both TRP14 and Trx1 inhibit the pathways of nuclear factor-κB (NF-κB), mitogen-activated protein kinases, and apoptosis in cells stimulated with tumor necrosis factor-α (TNF-α), but they appear to do so by acting on target proteins, some of which do not overlap. TRP14 inhibits the TNF-α-induced NF-κB activation to a greater extent than Trx1. The dynein light chain LC8 was identified as a new target of disulfide reductase activity of TRP14, and LC8 was shown to bind IκBα in a redox-dependent manner, thereby preventing its phosphorylation by IκB kinase. These findings elucidate the molecular mechanism by which NF-κB activation is regulated through TRP14.

Original languageEnglish
Pages (from-to)1294-1303
Number of pages10
JournalFree Radical Biology and Medicine
Volume47
Issue number9
DOIs
StatePublished - 1 Nov 2009

Keywords

  • Apoptosis
  • Cysteine oxidation
  • Disulfide reductase
  • Dynein light chain LC8
  • Mitogen-activated protein kinases
  • Nuclear factor-κB
  • Redox regulation
  • Thioredoxin family
  • Thioredoxin-related protein 14
  • Tumor necrosis factor-α

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