TY - JOUR
T1 - GOSPEL
T2 - a neuroprotective protein that binds to GAPDH upon S-nitrosylation.
AU - Sen, Nilkantha
AU - Hara, Makoto R.
AU - Ahmad, Abdullah Shafique
AU - Cascio, Matthew B.
AU - Kamiya, Atsushi
AU - Ehmsen, Jeffrey T.
AU - Aggrawal, Nishant
AU - Hester, Lynda
AU - Doré, Sylvain
AU - Snyder, Solomon H.
AU - Sawa, Akira
N1 - Funding Information:
This work was supported by United States Public Health Service grants MH-084018 and MH-069853 (A.S.); DA-00266 (S.H.S.); and Research Scientist Award DA-00074 (S.H.S.); and grants from the Stanley, National Alliance for Research in Schizophrenia and Affective Disorders, Core Huntington's Disease Initiative, and S-R Foundations (A.S.). We thank Yukiko L. Lema for preparing figures and organizing the manuscript. We appreciate technical assistance by Mr. S. Seshadri, Mr. J. Park, Ms. X. Luo, and Ms. L. Hanle.
PY - 2009/7/16
Y1 - 2009/7/16
N2 - 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.
AB - 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.
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U2 - 10.1016/j.neuron.2009.05.024
DO - 10.1016/j.neuron.2009.05.024
M3 - Article
C2 - 19607794
AN - SCOPUS:68349098976
SN - 0896-6273
VL - 63
SP - 81
EP - 91
JO - Neuron
JF - Neuron
IS - 1
ER -