Human Molecular Genetics Advance Access originally published online on August 8, 2008
Human Molecular Genetics 2008 17(21):3357-3367; doi:10.1093/hmg/ddn230
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Synergistic activation of the human MnSOD promoter by DJ-1 and PGC-1
: regulation by SUMOylation and oxidation
Department of Neurology, Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA
* To whom correspondence should be addressed at: Department of Neurology, Caritas St Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge St, CBR4, Boston, MA 02135, USA. Tel: +1 6177892935; Fax: +1 6177893111; Email: Jin.Xu{at}tufts.edu
Received July 1, 2008; Revised July 28, 2008; Accepted August 3, 2008
Oxidative stress contributes to the development of neurodegenerative diseases. DJ-1, a protein genetically linked to Parkinosn's disease (PD), has been implicated in oxidative stress defense and transcriptional regulation. However, it is unclear whether these two aspects of the DJ-1 function are connected. Here, we show that the inactivation of DJ-1 causes decreased expression of the human MnSOD. DJ-1 stimulates the activity of a master regulator of mitochondrial biogenesis and stress response, peroxisome proliferator-activated receptor-
co-activator 1
(PGC-1), in the transcription of the MnSOD. Although DJ-1 does not interact with PGC-1 directly, it inhibits the SUMOylation of a transcriptional repressor, pyrimidine tract-binding protein-associated splicing factor (PSF). PSF binds PGC-1 and suppresses its transcriptional activity. In contrast, a SUMOylation-deficient PSF mutant exhibits reduced binding to PGC-1 and promotes its activity. SUMO-specific isopeptidase SENP-1 further enhances the synergy between DJ-1 and PGC-1, whereas an SUMO E3 ligase protein inhibitor of activated STAT Y completely blocks the synergy. Conversely, oxidative modification renders DJ-1 unable to inhibit SUMOylation, resulting in attenuated transcriptional synergy between DJ-1 and PGC-1. Therefore, our results validate DJ-1 as a transcriptional regulator in mitochondrial oxidative stress response and imply that the oxidation-mediated functional impairment of DJ-1 leads to gradual dysregulation of the SUMO pathway. Consequent abnormal mitochondrial gene expression may contribute to the development of sporadic PD.