Abstract
We recently reported a cell death cascade whereby cellular stressors activate nitric oxide formation leading to S-nitrosylation of GAPDH that binds to Siah and translocates to the nucleus. The nuclear GAPDH/Siah complex augments p300/CBP-associated acetylation of nuclear proteins, including p53, which mediate cell death. We report a 52 kDa cytosolic protein, GOSPEL, which physiologically binds GAPDH, in competition with Siah, retaining GAPDH in the cytosol and preventing its nuclear translocation. GOSPEL is neuroprotective, as its overexpression prevents NMDA-glutamate excitotoxicity while its depletion enhances death in primary neuron cultures. S-nitrosylation of GOSPEL at cysteine 47 enhances GAPDH-GOSPEL binding and the neuroprotective actions of GOSPEL. In intact mice, virally delivered GOSPEL selectively diminishes NMDA neurotoxicity. Thus, GOSPEL may physiologically regulate the viability of neurons and other cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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2',5'-Oligoadenylate Synthetase / genetics
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2',5'-Oligoadenylate Synthetase / metabolism
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Animals
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Binding, Competitive / drug effects
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Brain
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cells, Cultured
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Disease Models, Animal
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Embryo, Mammalian
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Excitatory Amino Acid Agonists / pharmacology
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Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism*
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Green Fluorescent Proteins / genetics
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Humans
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MPTP Poisoning / prevention & control*
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Mice
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Mice, Knockout
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Molecular Weight
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Mutation
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N-Methylaspartate / pharmacology
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nerve Tissue Proteins / therapeutic use*
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Neurons / drug effects
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Neurons / metabolism*
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Neuroprotective Agents / pharmacology
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Neuroprotective Agents / therapeutic use*
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Nitric Oxide Synthase Type I / deficiency
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Nuclear Proteins / metabolism
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Protein Binding / drug effects
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Protein Transport / drug effects
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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S-Nitrosoglutathione / pharmacology
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Transfection / methods
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Two-Hybrid System Techniques
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Ubiquitin-Protein Ligases / metabolism
Substances
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Carrier Proteins
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Excitatory Amino Acid Agonists
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Nerve Tissue Proteins
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Neuroprotective Agents
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Nuclear Proteins
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RNA, Messenger
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RNA, Small Interfering
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Green Fluorescent Proteins
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S-Nitrosoglutathione
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N-Methylaspartate
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Nitric Oxide Synthase Type I
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Glyceraldehyde-3-Phosphate Dehydrogenases
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Ubiquitin-Protein Ligases
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seven in absentia proteins
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OAS1 protein, human
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2',5'-Oligoadenylate Synthetase