Abstract
Nucleoside diphosphate kinases (NDPK) are ubiquitous enzymes that catalyze the reversible phosphotransfer of γ-phosphates between di- and triphosphonucleosides. NDPK-D (Nm23-H4) is the only member of the NDPK family with a mitochondrial targeting sequence. Despite the high expression of NDPK-D in the developing central nervous system, its function remains to be determined. In this study, we show that NDPK-D knockdown induces apoptosis in neuroblastoma cells as well as in mouse cortex, suggesting that NDPK-D is required for neuronal survival. We identified NDPK-D as a binding partner of NAD+-dependent histone deacetylase, SIRT1, by yeast two-hybrid screening. NDPK-D co-localized with SIRT1, and the association of these molecules was confirmed by co-immunoprecipitation. Inhibition of SIRT1 increases the acetylation of NDPK-D. Overexpression of NDPK-D along with SIRT1, or mutation in the acetylated lysine residues in NDPK-D, increases its nuclear accumulation. Furthermore, the NDPK-D acetylation-mimic mutant increased apoptosis in N1E-115 cells. Our data demonstrate that acetylation regulates the shuttling of NDPK-D between nucleus and cytoplasm, and increased acetylation of NDPK-D causes apoptosis.
Highlights
The sirtuins are a conserved class of proteins, which possess NAD+-dependent deacetylase and adenosine diphosphate (ADP)-ribosyl transferase activity [1,2,3,4,5]
We found that nucleoside diphosphate kinases D (NDPK-D/Nm23-H4) encoded by the Nme4 gene [33], is a novel SIRT1 binding partner
We first examined the Nucleoside diphosphate kinases (NDPK)-D expression profile by real-time PCR, using total RNA extracted from mouse brains at various developmental stages
Summary
The sirtuins are a conserved class of proteins, which possess NAD+-dependent deacetylase and adenosine diphosphate (ADP)-ribosyl transferase activity [1,2,3,4,5]. Seven sirtuin homologs (SIRT1-7) identified are categorized into four classes based on their DNA sequence. SIRT1, the mammalian homolog of Sir belongs to class I sirtuins [8]. Because the activity of SIRT1 depends on NAD+, the energy status of the cell and nutrient deprivation such as fasting and caloric restriction may affect its function [9]. SIRT1 mediates diverse aspects of cells, including survival, differentiation, and metabolism, through the deacetylation of target molecules [10, 11].
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