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PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death

 Hyo-Kyoung Choi  ;  Youngsok Choi  ;  HeeBum Kang  ;  Eun-jin Lim  ;  Soo-Yeon Park  ;  Hyun-Seob Lee  ;  Ji-Min Park  ;  Jisook Moon  ;  Yoon-Jung Kim  ;  Insup Choi  ;  Eun-Hye Joe  ;  Kyung-Chul Choi  ;  Ho-Geun Yoon 
 HUMAN MOLECULAR GENETICS, Vol.24(4) : 1127-1141, 2015 
Journal Title
Issue Date
Acetylation/drug effects ; Animals ; Caspase 7/metabolism ; Cell Death/genetics ; Cell Line ; Cytoplasm/metabolism ; Dopaminergic Neurons/metabolism* ; Dopaminergic Neurons/pathology ; Enzyme Activation ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism* ; Humans ; Hydrogen Peroxide/pharmacology ; Mice ; Organ Specificity ; Phosphorylation ; Protein Kinases/genetics ; Protein Kinases/metabolism* ; Proteolysis ; Tumor Suppressor Protein p53/metabolism
dopamine ; hydrogen peroxide ; phosphorylation ; neuron death ; pink1 gene
Deciphering the molecular basis of neuronal cell death is a central issue in the etiology of neurodegenerative diseases, such as Parkinson's and Alzheimer's. Dysregulation of p53 levels has been implicated in neuronal apoptosis. The role of histone deacetylase 3 (HDAC3) in suppressing p53-dependent apoptosis has been recently emphasized; however, the molecular basis of modulation of p53 function by HDAC3 remains unclear. Here we show that PTEN-induced putative kinase 1 (PINK1), which is linked to autosomal recessive early-onset familial Parkinson's disease, phosphorylates HDAC3 at Ser-424 to enhance its HDAC activity in a neural cell-specific manner. PINK1 prevents H2O2-induced C-terminal cleavage of HDAC3 via phosphorylation of HDAC3 at Ser-424, which is reversed by protein phosphatase 4c. PINK1-mediated phosphorylation of HDAC3 enhances its direct association with p53 and causes subsequent hypoacetylation of p53. Genetic deletion of PINK1 partly impaired the suppressive role of HDAC3 in regulating p53 acetylation and transcriptional activity. However, depletion of HDAC3 fully abolished the PINK1-mediated p53 inhibitory loop. Finally, ectopic expression of phosphomometic-HDAC3(S424E) substantially overcomes the defective action of PINK1 against oxidative stress in dopaminergic neuronal cells. Together, our results uncovered a mechanism by which PINK1-HDAC3 network mediates p53 inhibitory loop in response to oxidative stress-induced damage.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kang, Hee Bum(강희범)
Park, Soo Yeon(박수연) ORCID logo https://orcid.org/0000-0003-3743-9554
Yoon, Ho Geun(윤호근) ORCID logo https://orcid.org/0000-0003-2718-3372
Choi, Hyo Kyoung(최효경)
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