Distinct roles of thioredoxin in the cytoplasm and in the nucleus - A two-step mechanism of redox regulation of transcription factor NF-kappa B

Oxidative stresses such as UV irradiation to mammalian cells triggers a var iety of oxistress responses including activation of transcription factors. Recently, activation of nuclear factor-kappa B (NF-kappa B) has been shown to be under oxidoreduction (redox) regulation controlled by thioredoxin (TR X), which is one of major endogenous redox-regulating molecules with thiol reducing activity. In order to elucidate where in the cellular compartment TRX participates in NF-kappa B regulation, we investigated the intracellula r localization of TRX. UVB irradiation induced translocation of TRX from th e cytoplasm into the nucleus. In our in vitro diamide-induced cross-linking study, we showed that TRX can associate directly with NF-kappa B p50. Over expression of wild-type TRX suppressed induction of luciferase activity und er NF-kappa B-binding sites in response to UV irradiation compared with the mock transfectant. In contrast, overexpression of nuclear-targeted TRX enh anced the luciferase activity. Thus, TRX seems to play dual and opposing ro les in the regulation of NF-kappa B. In the cytoplasm, it interferes with t he signals to I kappa B kinases and blocks the degradation of I kappa B. In the nucleus, however, TRX enhances NF-kappa KB transcriptional activities by enhancing its ability to bind DNA. This two-step TRX-dependent regulatio n of the NF-kappa B complex may be a novel activation mechanism of redox-se nsitive transcription factors.