title: Thioredoxin-dependent regulation of AIF-mediated DNA damage.
abstract: 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 cytosolic/nuclear Trx1 and apoptosis inducing factor (AIF), and the redox sensitivity and biological significance of the Trx-AIF interaction was characterized. Cytosolic Trx1 but not mitochondrial Trx2 was observed to interact with AIF under physiological conditions and Trx1's active site cysteines were crucial for the interaction. Under oxidative stress conditions, Trx-AIF 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 AIF was re-established time-dependently, which underpins the biological relevance of a Trx-dependent redox regulation of AIF-mediated cell death. Indeed, in times of oxidative stress, nuclear translocation of AIF was found to occur concurrently with perturbations to the Trx-AIF interaction. Once localized in the nucleus, reduced Trx1 hindered the interaction between AIF and DNA, thereby bringing about an attenuation of AIF-mediated DNA damage. In conclusion, characterization of the Trx-AIF interaction has led to an understanding of the effect of reduced Trx1 on possibly regulating AIF-dependent cell death through impeding AIF-mediated DNA damage. Importantly, identification of the novel interaction between Trx1 and AIF 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.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, S117543, Republic ofSingapore.
authors.forename: Sandeep B
authors.initials: SB
authors.lastname: Shelar
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, S117543, Republic ofSingapore.
authors.forename: Kamila K
authors.initials: KK
authors.lastname: Kaminska
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, S117543, Republic ofSingapore.
authors.forename: Shridhivya A
authors.initials: SA
authors.lastname: Reddy
authors.affiliation: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A⁎STAR), S138648, Republic of Singapore.
authors.forename: Dilip
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, S117543, Republic ofSingapore.
authors.forename: Chong-Teik
authors.initials: CT
authors.lastname: Tan
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, S117543, Republic ofSingapore.
authors.forename: Victor C
authors.initials: VC
authors.lastname: Yu
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Holmgren
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, S117597, Republic of Singapore.
authors.forename: Thilo
authors.initials: T
authors.lastname: Hagen
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, S117543, Republic ofSingapore. Electronic address: phaceh@nus.edu.sg.
authors.forename: Eng-Hui
authors.initials: EH
authors.lastname: Chew
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008928:Mitochondria; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics*; D060066:Protein Interaction Maps / Q000235:genetics*; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism
chemical_list: C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; C491203:TXN protein, human; D013879:Thioredoxins
keywords: Apoptosis inducing factor; Oxidative stress; Protein-protein interaction; Thioredoxin