Thioredoxin-dependent regulation of AIF-mediated DNA damage

The thioredoxin (Trx) system is one major redox system in mammalian cells. One of its component, Trx, is involved in redox homeostasis and many cellular biological processes through participating in disulfide reduction, S-nitrosylation/S-denitrosylation reactions and protein-protein interactions. In this study, we report the identification of a novel interaction between cytosolicinuclear Trx1 and apoptosis inducing factor (RIF), and the redox sensitivity and biological significance of the Trx-AIF interaction was characterized. Cytosolic Trxl but not mitochondrial Trx2 was observed to interact with RIP under physiological conditions and Trxl's active site cysteines were crucial for the interaction. Under oxidative stress conditions, Trx-AlF interaction was disrupted. When the treated cells were allowed to recover from oxidative stress by means of removal of the oxidants, interaction between Trx1 and NE was re-established time-dependently, which underpins the biological relevance of a Trx-dependent redox regulation of AlF-mediated cell death. Indeed, in times of oxidative stress, nuclear translocation of ALF was found to occur concurrently with perturbations to the Trx-AlF interaction. Once localized in the nucleus, reduced Trxl hindered the interaction between ALF and DNA, thereby bringing about an attenuation of ALEmediated DNA damage. In conclusion, characterization of the Trx-AIF interaction has led to an understanding of the effect of reduced Trxl on possibly regulating AlF-dependent cell death through impeding AIF-mediated DNA damage. Importantly, identification of the novel interaction between Trxl and RIP has provided opportunities to design and develop therapeutically relevant strategies that either promote or prevent this protein-protein interaction for the treatment of different disease states. (C) 2015 Published by Elsevier Inc.