Synergistic activation of the human MnSOD promoter by DJ-1 and PGC-1α: regulation by SUMOylation and oxidation

Abstract

Oxidative stress contributes to the development of neurodegenerative diseases. DJ-1, a protein genetically linked to Parkinson'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-gamma co-activator 1alpha (PGC-1alpha), in the transcription of the MnSOD. Although DJ-1 does not interact with PGC-1alpha directly, it inhibits the SUMOylation of a transcriptional repressor, pyrimidine tract-binding protein-associated splicing factor (PSF). PSF binds PGC-1alpha and suppresses its transcriptional activity. In contrast, a SUMOylation-deficient PSF mutant exhibits reduced binding to PGC-1alpha and promotes its activity. SUMO-specific isopeptidase SENP-1 further enhances the synergy between DJ-1 and PGC-1alpha, 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-1alpha. 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.