Disruption of the nuclear p53-GAPDH complex protects against ischemia-induced neuronal damage

Dongxu Zhai,Min Wang,Fang Liu,Kyle Chin

doi:10.1186/1756-6606-7-20

Abstract

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is conventionally considered a critical enzyme that involves in glycolysis for energy production. Recent previous studies have suggested that GAPDH is important in glutamate-induced neuronal excitotoxicity, while accumulated evidence also demonstrated that GAPDH nuclear translocation plays a critical role in cell death. However, the molecular mechanisms underlying this process remain largely unknown. In this study, we showed that GAPDH translocates to the nucleus in a Siah1-dependent manner upon glutamate stimulation. The nuclear GAPDH forms a protein complex with p53 and enhances p53 expression and phosphorylation. Disruption of the GAPDH-p53 interaction with an interfering peptide blocks glutamate-induced cell death and GAPDH-mediated up-regulation of p53 expression and phosphorylation. Furthermore, administration of the interfering peptide in vivo protects against ischemia-induced cell death in rats subjected to tMCAo. Our data suggest that the nuclear p53-GAPDH complex is important in regulating glutamate-mediated neuronal death and could serve as a potential therapeutic target for ischemic stroke treatment.

Highlights

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is traditionally thought to be a critical enzyme for glycolysis, and an important protein in energy production
Nuclear GAPDH forms a complex with p53 that leads to the activation of p53-mediated cell death pathway
Glutamate induces GAPDH nuclear translocation in a Siah1-dependent manner Previous studies have demonstrated that glutamate stimulation promotes GAPDH nuclear translocation, which leads to the activation of the cell death pathway [4]

Summary

Introduction

GAPDH is traditionally thought to be a critical enzyme for glycolysis, and an important protein in energy production. Recent evidence suggests that GAPDH is involved in apoptosis, as indicated by changes in GAPDH expression and subcellular localization during apoptosis [1,2,3,4]. GAPDH is not restricted to the cytosol, but it is found in the nucleus, plasma membrane and extracellular space. The subcellular localization of GAPDH may be important for the multifuntional role of GAPDH. Membrane-associated GAPDH binds to tubulin, thereby regulating polymerization and bundling of microtubules near the cell membrane. This suggests that GAPDH is involved in the organization of subcellular organelles [5]. Release of tubulin from membraneassociated GAPDH facilitates the fusion of vesicles to the plasma membrane [6]. GAPDH can be secreted from cells, where it can associate with

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