S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding
Copyright policy )S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) influences cytotoxicity, translocating to the nucleus during apoptosis. Here we report a signalling pathway in which nitric oxide (NO) generation that follows apoptotic stimulation elicits S-nitrosylation of GAPDH, which triggers binding to Siah1 (an E3 ubiquitin ligase), nuclear translocation and apoptosis. S-nitrosylation of GAPDH augments its binding to Siah1, whose nuclear localization signal mediates translocation of GAPDH. GAPDH stabilizes Siah1, facilitating its degradation of nuclear proteins. Activation of macrophages by endotoxin and of neurons by glutamate elicits GAPDH-Siah1 binding, nuclear translocation and apoptosis, which are prevented by NO deletion. The NO-S-nitrosylation-GAPDH-Siah1 cascade may represent an important molecular mechanism of cytotoxicity.
- Johns Hopkins Medicine United States
- Johns Hopkins University School of Medicine United States
Cell Nucleus, Lipopolysaccharides, Mice, Knockout, Neurons, Cytoplasm, N-Methylaspartate, Macrophages, Apoptosis, Nerve Tissue Proteins, Models, Biological, Cell Line, Mice, Microscopy, Fluorescence, Cell Line, Tumor, Mutation, Animals, Humans, Cysteine, Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), Cells, Cultured
Cell Nucleus, Lipopolysaccharides, Mice, Knockout, Neurons, Cytoplasm, N-Methylaspartate, Macrophages, Apoptosis, Nerve Tissue Proteins, Models, Biological, Cell Line, Mice, Microscopy, Fluorescence, Cell Line, Tumor, Mutation, Animals, Humans, Cysteine, Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), Cells, Cultured
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