DJ-1 transcriptionally up-regulates the human tyrosine hydroxylase by inhibiting the sumoylation of pyrimidine tract-binding protein-associated splicing factor.
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.
Zhong
Nan
N
Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston 02135, Massachusetts.
Kim
Christina Y
CY
Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston 02135, Massachusetts.
Rizzu
Patrizia
P
Department of Human Genetics, Vrise University (VU) University Medical Center and VU University, Amsterdam, The Netherlands.
Geula
Changiz
C
Laboratory for Neurodegenerative and Aging Research, Department of Medicine, Harvard Medical School and Division of Gerontology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115.
Porter
Douglas R
DR
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111.
Pothos
Emmanuel N
EN
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111.
Squitieri
Ferdinando
F
Neurogenetics Unit, IRCCS Neuromed, 86077 Pozzilli, Italy.
Heutink
Peter
P
Department of Human Genetics, Vrise University (VU) University Medical Center and VU University, Amsterdam, The Netherlands.
Xu
Jin
J
Department of Neurology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston 02135, Massachusetts. Electronic address: Jin.Xu@tufts.edu.
D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007980:Levodopa / Q000096:biosynthesis; D008214:Lymphocytes / Q000378:metabolism; D015513:Oncogene Proteins / Q000096:biosynthesis*; D000072670:PTB-Associated Splicing Factor; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D000071617:Protein Deglycase DJ-1; D011743:Pyrimidines / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis* / Q000737:chemistry; D015854:Up-Regulation
D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D000072670:PTB-Associated Splicing Factor; D011743:Pyrimidines; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; C105131:PARK7 protein, human; D000071617:Protein Deglycase DJ-1