Interaction of DJ-1 with Daxx inhibits apoptosis signal-regulating kinase 1 activity and cell death.
Investigations into the cellular and molecular biology of genes that cause inherited forms of Parkinson's disease, as well as the downstream pathways that they trigger, shed considerable light on our understanding the fundamental determinants of life and death in dopaminergic neurons. Homozygous deletion or missense mutation in DJ-1 results in autosomal recessively inherited Parkinson's disease, suggesting that wild-type DJ-1 has a favorable role in maintaining these neurons. Here, we show that DJ-1 protects against oxidative stress-induced cell death, but that its relatively modest ability to quench reactive oxygen species is insufficient to account for its more robust cytoprotective effect. To elucidate the mechanism of this cell-preserving function, we have screened out the death protein Daxx as a DJ-1-interacting partner. We demonstrate that wild-type DJ-1 sequesters Daxx in the nucleus, prevents it from gaining access to the cytoplasm, from binding to and activating its effector kinase apoptosis signal-regulating kinase 1, and therefore, from triggering the ensuing death pathway. All these steps are impaired by the disease-causing L166P mutant isoform of DJ-1. These findings suggest that the regulated sequestration of Daxx in the nucleus and keeping apoptosis signal-regulating kinase 1 activation in check is a critical mechanism by which DJ-1 exerts its cytoprotective function.
Junn
Eunsung
E
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.
Taniguchi
Hiroyuki
H
Jeong
Byeong Seon
BS
Zhao
Xin
X
Ichijo
Hidenori
H
Mouradian
M Maral
MM
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D056970:Co-Repressor Proteins; D017931:DNA Primers; D005452:Fluoresceins; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D018832:Molecular Chaperones; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D000071617:Protein Deglycase DJ-1; D034741:RNA, Small Interfering / Q000235:genetics; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D017931:DNA Primers; D005452:Fluoresceins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D034741:RNA, Small Interfering; C029569:diacetyldichlorofluorescein; D048848:MAP Kinase Kinase Kinase 5; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1