Thioredoxin-related protein 14, a new member of the thioredoxin family with disulfide reductase activity: implication in the redox regulation of TNF-alpha signaling.
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-kappaB (NF-kappaB), mitogen-activated protein kinases, and apoptosis in cells stimulated with tumor necrosis factor-alpha (TNF-alpha), but they appear to do so by acting on target proteins, some of which do not overlap. TRP14 inhibits the TNF-alpha-induced NF-kappaB 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 IkappaBalpha in a redox-dependent manner, thereby preventing its phosphorylation by IkappaB kinase. These findings elucidate the molecular mechanism by which NF-kappaB activation is regulated through TRP14.
Jeong
Woojin
W
Department of Life Science, Division of Life and Pharmaceutical Sciences, and Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul 120-750, Korea. jeongw@ewha.ac.kr
Jung
Yuyeon
Y
Kim
Hojin
H
Park
Sun Joo
SJ
Rhee
Sue Goo
SG
D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology*; D013879:Thioredoxins / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016328:NF-kappa B; C482341:TXNDC17 protein, human; D014409:Tumor Necrosis Factor-alpha; D013879:Thioredoxins