DJ-1 protects against oxidative damage by regulating the thioredoxin/ASK1 complex.
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(2)O(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(2)O(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.
Im
Joo-Young
JY
Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Lee
Kang-Woo
KW
Junn
Eunsung
E
Mouradian
M Maral
MM
D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D002460:Cell Line; D003545:Cysteine / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics / Q000502:physiology; D015513:Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics*; D054464:Peroxiredoxins; D010957:Plasmids; D000071617:Protein Deglycase DJ-1; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D015513:Oncogene Proteins; D013879:Thioredoxins; D054464:Peroxiredoxins; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D003545:Cysteine
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