REGULATORY ROLE FOR A NOVEL HUMAN THIOREDOXIN PEROXIDASE IN NF-KAPPA-B ACTIVATION

Reduction-oxidation (redox) plays a critical role in NF-kappa B activa tion. Diverse stimuli appear to utilize reactive oxygen species (e.g. hydrogen peroxide) as common effecters for activating NF-kappa B. Anti oxidants govern intracellular redox status, and many such molecules ca n reduce H2O2.,, However, functionally, it does appear that different antioxidants are variously selective for redox regulation of certain t ranscription factors such as NF-kappa B, For NF-kappa B, thioredoxin h as been described to be a more potent antioxidant than either glutathi one or N-acetylcysteine. Thioredoxin peroxidase is the immediate enzym e 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 descr ibe a new human thioredoxin peroxidase, antioxidant enzyme AOE372, ide ntified by virtue of its protein-protein interaction with the product of a proliferation association gene, pag, which is also a thiol specif ic antioxidant, In human cells, AOE372 defines a redox pathway that sp ecifically regulates NF-kappa B activity via a modulation of I kappa B -alpha phosphorylation in the cytoplasm, We show that AOE372 activity is regulated through either home-or heterodimerization with other thio l peroxidases, implicating subunit assortment as a mechanism for regul ating antioxidant specificities, AOE372 function suggests thioredoxin peroxidase as an immediate regulator of H2O2-mediated activation of NF -kappa B.