GOSPEL: a neuroprotective protein that binds to GAPDH upon S-nitrosylation.
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.
Sen
Nilkantha
N
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Hara
Makoto R
MR
Ahmad
Abdullah Shafique
AS
Cascio
Matthew B
MB
Kamiya
Atsushi
A
Ehmsen
Jeffrey T
JT
Agrawal
Nishant
N
Aggrawal
Nishant
N
Hester
Lynda
L
Doré
Sylvain
S
Snyder
Solomon H
SH
Sawa
Akira
A
D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D020267:MPTP Poisoning / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D008970:Molecular Weight; D009154:Mutation; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000098563:Seven in Absentia Proteins
D002352:Carrier Proteins; D018690:Excitatory Amino Acid Agonists; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D026422:S-Nitrosoglutathione; D016202:N-Methylaspartate; D052248:Nitric Oxide Synthase Type I; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins; C475085:OAS1 protein, human; D015088:2',5'-Oligoadenylate Synthetase