DJ-1 protects against oxidative damage by regulating the thioredoxin/ASK1 complex

• Published in: Neuroscience research 2010-07, Vol.67 (3), p.203-208
• Main Authors: Im, Joo-Young, Lee, Kang-Woo, Junn, Eunsung, Mouradian, M. Maral
• Format: Article
• Language: English
• Subjects: Animals; ASK1; Blotting, Western; Cell Death; Cell Line; Cysteine - physiology; DJ-1; Fibroblasts - physiology; Gene Expression Regulation; Humans; Immunoprecipitation; MAP Kinase Kinase Kinase 5 - genetics; MAP Kinase Kinase Kinase 5 - metabolism; Mice; Mutation - genetics; Mutation - physiology; Oncogene Proteins - genetics; Oncogene Proteins - physiology; Oxidative stress; Oxidative Stress - genetics; Parkinson's disease (PD); Peroxiredoxins; Plasmids; Protein Deglycase DJ-1; Thioredoxin 1; Thioredoxins - genetics; Thioredoxins - metabolism; Transfection
• ISSN: 0168-0102; 1872-8111
• DOI: 10.1016/j.neures.2010.04.002

DJ-1 is a multifunctional protein linked to recessively inherited Parkinson's disease (PD) due to loss of function mutations. Among its activities is anti-oxidant property leading to cytoprotection under oxidative stress conditions. A key effector of oxidant-induced cell death is the MAP3 kinase apoptosis signal-regulating kinase 1 (ASK1) which is bound to and inhibited by thioredoxin 1 (Trx1) under basal conditions. Upon oxidative stimuli, however, ASK1 dissociates from this physiological inhibitor and is activated. In the present study, we investigated the role of DJ-1 in regulating Trx1/ASK1 interaction. Over-expression of DJ-1 suppressed ASK1 activation in response to H 2O 2 in a time-dependent manner. Wild-type DJ-1, but not the PD-associated L166P mutant, prevented the dissociation of ASK1 from Trx1 in response to H 2O 2. Among cysteine mutants of DJ-1, C46S, C53S, and C106S, only C106S failed to inhibit this dissociation implying that cysteine 106 is essential for Trx1/ASK1 regulation. Furthermore, compared to wild-type mice, DJ-1 null mouse brain homogenates and embryonic fibroblasts were more susceptible to oxidant-induced dissociation of ASK1 from Trx1, activation of the downstream kinase c-Jun N-terminal kinase, and to cell death. These findings point to yet another mechanism through which DJ-1 has anti-oxidant and cytoprotective properties by regulating the Trx1/ASK1 complex and controlling the availability of ASK1 to effect apoptosis.