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

Nan Zhong,Christina Y Kim,Patrizia Rizzu,Changiz Geula,Douglas R Porter,Emmanuel N Pothos,Ferdinando Squitieri,Peter Heutink,Jin Xu

doi:10.1074/jbc.m601935200

Abstract

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.

Highlights

Parkinson disease (PD)4 is a common progressive movement disease characterized by the selective loss of dopaminergic neurons and the decrease of striatal dopamine levels [1]
We have recently demonstrated that DJ-1 forms complexes with nuclear proteins pyrimidine tract-binding protein-associated splicing factor (PSF) and p54nrb [7], two proteins that are highly expressed in the brain and affect RNA metabolism and transcription
DJ-1 and PSF Transcriptionally Regulate the Human TH Promoter—Since we have shown that DJ-1 is a transcriptional co-activator, we examined whether DJ-1 regulated the expression of genes involved in dopaminergic neurotransmission, such as tyrosine hydroxylase, the rate-limiting enzyme that converts tyrosine to the dopamine precursor L-DOPA

Summary

Introduction

Parkinson disease (PD)4 is a common progressive movement disease characterized by the selective loss of dopaminergic neurons and the decrease of striatal dopamine levels [1]. 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. To mimic the loss-of-function effects as seen in PD patients with DJ-1 mutations, we used DJ-1-specific siRNA constructs to inhibit the synthesis of endogenous DJ-1 in two human dopaminergic neuroblastoma cell lines, CHP-212 and SH-SY5Y cells.

Results

Conclusion