Download PINK1 positively regulates HDAC3 to suppress p53

PINK1 positively regulates HDAC3 to suppress p53-mediated neuronal cell
death
Ho-Geun Yoon, Ph.D., Associate Professor
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine
Dysregulation of p53 has been implicated in neuronal cell death. 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 cytoplasmic PTEN-induced
putative kinase 1 (PINK1) directly binds to and phosphorylates HDAC3 at Ser-424 to enhance its histone
deacetylase activity. We demonstrate that PINK1 prevents H2O2-induced C-terminal cleavage of HDAC3 by
inhibiting caspase-7 activity, which was reversed by protein phosphatase 4c (PP4c). PINK1-mediated
phosphorylation of HDAC3 enhances its direct association with p53 and causes subsequent hypoacetylation of
p53. We found that HDAC3 play an important role in recruiting multiple HDAC proteins for p53
hypoacetylation. Depletion of HDAC3 abolished the suppressive role of PINK1 in regulating p53 acetylation
and transcriptional activity. However, depletion or pathogenic mutation of PINK1 partly impaired the
suppressive role of HDAC3 in the regulation of p53 acetylation and transcriptional activity, suggesting that
PINK1 is upstream of HDAC3-mediated inhibition of p53 function. Strikingly, HDAC3 restoration recovered
the antagonistic action of PINK1 against oxidative stress-induced DNA damage. Together, our results uncovered
a mechanism by which PINK1-HDAC3 network mediates p53 inhibitory loop in response to oxidative stressinduced damage.