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Hum Mol Genet. 2015 Feb 15;24(4):1127-41. doi: 10.1093/hmg/ddu526. Epub 2014 Oct 9.

PINK1 positively regulates HDAC3 to suppress dopaminergic neuronal cell death.

Author information

1
Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, South Korea.
2
Fertility Center of CHA General Hospital, CHA Research Institute and.
3
Applied Bioscience, College of Life Science, CHA University, Seoul 135-081, South Korea.
4
ILSONG Institute of Life Science, Hallym University, Rm 607, ILSONG Bldg, 1605-4 Gwanyang-dong, Dongan-gu, Anyang, Gyonggi-do 431-060, South Korea.
5
Department of Biomedical Sciences, Neuroscience Graduate Program, Ajou University School of Medicine, Suwon 443-380, South Korea and.
6
Department of Medicine, Graduate School, University of Ulsan College of Medicine, 388-1 Poongnap-dong, Songpa-gu, Seoul 138-736, South Korea choikc75@ulsan.ac.kr yhgeun@yuhs.ac.
7
Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, South Korea, choikc75@ulsan.ac.kr yhgeun@yuhs.ac.

Abstract

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.

PMID:
25305081
DOI:
10.1093/hmg/ddu526
[Indexed for MEDLINE]

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