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Human Molecular Genetics Advance Access published online on August 8, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn230
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Synergistic Activation of the Human MnSOD Promoter by DJ-1 and PGC-1{alpha}: Regulation by SUMOylation and Oxidation

Nan Zhong and Jin Xu*

Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA 02135, USA

* Correspondence: Jin Xu, Ph.D. Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, 736 Cambridge St, CBR4, Boston, MA 02135, USA Phone: (617)789-2935 Fax: (617)789-3111 E-mail: 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, PPAR{gamma} coactivator 1 {alpha} (PGC-1{alpha}), in the transcription of the MnSOD. Although DJ-1 does not interact with PGC-1{alpha} directly, it inhibits the SUMOylation of a transcriptional repressor, pyrimidine tract-binding protein-associated splicing factor (PSF). PSF binds PGC-1{alpha} and suppresses its transcriptional activity. In contrast, a SUMOylation-deficient PSF mutant exhibits reduced binding to PGC-1{alpha} and promotes its activity. SUMO-specific isopeptidase SENP-1 further enhances the synergy between DJ-1 and PGC-1{alpha}, while an SUMO E3 ligase PIASy 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{alpha}. 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.


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