Regulatory role for a novel human thioredoxin peroxidase in NF-kappaB activation.
Reduction-oxidation (redox) plays a critical role in NF-kappaB activation. Diverse stimuli appear to utilize reactive oxygen species (e.g. hydrogen peroxide) as common effectors for activating NF-kappaB. Antioxidants govern intracellular redox status, and many such molecules can reduce H2O2. However, functionally, it does appear that different antioxidants are variously selective for redox regulation of certain transcription factors such as NF-kappaB. For NF-kappaB, thioredoxin has been described to be a more potent antioxidant than either glutathione or N-acetylcysteine. Thioredoxin peroxidase is the immediate enzyme that links reduction of H2O2 to thioredoxin. Several putative human thioredoxin peroxidases have been identified using recursive sequence searches/alignments with yeast or prokaryotic enzymes. None has been characterized in detail for intracellular function(s). Here, we describe a new human thioredoxin peroxidase, antioxidant enzyme AOE372, identified by virtue of its protein-protein interaction with the product of a proliferation association gene, pag, which is also a thiol-specific antioxidant. In human cells, AOE372 defines a redox pathway that specifically regulates NF-kappaB activity via a modulation of IkappaB-alpha phosphorylation in the cytoplasm. We show that AOE372 activity is regulated through either homo- or heterodimerization with other thiol peroxidases, implicating subunit assortment as a mechanism for regulating antioxidant specificities. AOE372 function suggests thioredoxin peroxidase as an immediate regulator of H2O2-mediated activation of NF-kappaB.
Jin
D Y
DY
Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
Chae
H Z
HZ
Rhee
S G
SG
Jeang
K T
KT
D000595:Amino Acid Sequence; D000975:Antioxidants / Q000378:metabolism; D001483:Base Sequence; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D015658:HIV Infections / Q000201:enzymology; D015497:HIV-1; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins; D008969:Molecular Sequence Data; D008970:Molecular Weight; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D010084:Oxidation-Reduction; D010544:Peroxidases; D061105:Peroxiredoxin III; D054464:Peroxiredoxins; D010766:Phosphorylation; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D014018:Tissue Distribution
D000975:Antioxidants; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009363:Neoplasm Proteins; D011506:Proteins; D012333:RNA, Messenger; D000072000:NF-KappaB Inhibitor alpha; D010544:Peroxidases; C516115:PRDX3 protein, human; D061105:Peroxiredoxin III; D054464:Peroxiredoxins