DJ-1 Transcriptionally Up-regulates the Human Tyrosine Hydroxylase by Inhibiting the Sumoylation of Pyrimidine Tract-binding Protein-associated Splicing Factor

• Published in: The Journal of biological chemistry 2006-07, Vol.281 (30), p.20940-20948
• Main Authors: Zhong, Nan, Kim, Christina Y., Rizzu, Patrizia, Geula, Changiz, Porter, Douglas R., Pothos, Emmanuel N., Squitieri, Ferdinando, Heutink, Peter, Xu, Jin
• Format: Article
• Language: English
• Subjects: Humans; Intracellular Signaling Peptides and Proteins; Levodopa - biosynthesis; Lymphocytes - metabolism; Oncogene Proteins - biosynthesis; Plasmids - metabolism; Promoter Regions, Genetic; Protein Binding; Protein Deglycase DJ-1; PTB-Associated Splicing Factor; Pyrimidines - chemistry; RNA, Small Interfering - metabolism; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - metabolism; Transcription, Genetic; Transcriptional Activation; Tyrosine 3-Monooxygenase - biosynthesis; Tyrosine 3-Monooxygenase - chemistry; Up-Regulation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M601935200

Loss-of-function mutations in DJ-1 cause a subset of familial Parkinson disease (PD). However, the mechanism underlying the selective vulnerability in dopaminergic pathway due to the inactivation of DJ-1 is unclear. Previously, we have reported that DJ-1 is a neuroprotective transcriptional co-activator interacting with the transcriptional co-repressor pyrimidine tract-binding protein-associated splicing factor (PSF). Here we show that DJ-1 and PSF bind and regulate the human tyrosine hydroxylase (TH) promoter. Inactivation of DJ-1 by small interference RNA (siRNA) results in decreased TH expression and l-DOPA production in human dopaminergic cell lines. Consistent with its role as a transcriptional regulator, DJ-1 specifically suppresses the global SUMO-1 modification. High molecular weight sumoylated protein species, including PSF, accumulate in the lymphoblast cells from the patients carrying pathogenic DJ-1 mutations. DJ-1 elevates the TH expression by inhibiting the sumoylation of PSF and preventing its sumoylation-dependent recruitment of histone deacetylase 1. Furthermore, siRNA silencing of DJ-1 decreases the acetylation of TH promoter-bound histones, and histone deacetylase inhibitors restore the DJ-1 siRNA-induced repression of TH. Therefore, our results suggest DJ-1 as a regulator of protein sumoylation and directly link the loss of DJ-1 expression and transcriptional dysfunction to impaired dopamine synthesis.