TY - JOUR
T1 - Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis
AU - Sen, Nilkantha
AU - Hara, Makoto R.
AU - Kornberg, Michael D.
AU - Cascio, Matthew B.
AU - Bae, Byoung Il
AU - Shahani, Neelam
AU - Thomas, Bobby
AU - Dawson, Ted M.
AU - Dawson, Valina L.
AU - Snyder, Solomon H.
AU - Sawa, Akira
N1 - Funding Information:
This work was supported by USPHS grants MH-069853 (A.S.); DA-00266, Research Scientist Award DA-00074 (S.H.S); NS-48206, NS-38377, DA-00226 (T.M.D, V.L.D) and grants from Stanley, NARSAD and S-R foundations (A.S.). We thank Yukiko L. Lema for preparing the figures and organizing the manuscript. We appreciate technical assistance provided by A. Kamiya.
PY - 2008/7
Y1 - 2008/7
N2 - Besides its role in glycolysis, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) initiates a cell death cascade. Diverse apoptotic stimuli activate inducible nitric oxide synthase (iNOS) or neuronal NOS (nNOS), with the generated nitric oxide (NO) S-nitrosylating GAPDH, abolishing its catalytic activity and conferring on it the ability to bind to Siah1, an E3-ubiquitin-ligase with a nuclear localization signal (NLS). The GAPDH-Siah1 protein complex, in turn, translocates to the nucleus and mediates cell death; these processes are blocked by procedures that interfere with GAPDH-Siah1 binding. Nuclear events induced by GAPDH to kill cells have been obscure. Here we show that nuclear GAPDH is acetylated at Lys 160 by the acetyltransferase p300/CREB binding protein (CBP) through direct protein interaction, which in turn stimulates the acetylation and catalytic activity of p300/CBP. Consequently, downstream targets of p300/CBP, such as p53 (Refs 10,11,12,13,14,15), are activated and cause cell death. A dominant-negative mutant GAPDH with the substitution of Lys 160 to Arg (GAPDH-K160R) prevents activation of p300/CBP, blocks induction of apoptotic genes and decreases cell death. Our findings reveal a pathway in which NO-induced nuclear GAPDH mediates cell death through p300/CBP.
AB - Besides its role in glycolysis, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) initiates a cell death cascade. Diverse apoptotic stimuli activate inducible nitric oxide synthase (iNOS) or neuronal NOS (nNOS), with the generated nitric oxide (NO) S-nitrosylating GAPDH, abolishing its catalytic activity and conferring on it the ability to bind to Siah1, an E3-ubiquitin-ligase with a nuclear localization signal (NLS). The GAPDH-Siah1 protein complex, in turn, translocates to the nucleus and mediates cell death; these processes are blocked by procedures that interfere with GAPDH-Siah1 binding. Nuclear events induced by GAPDH to kill cells have been obscure. Here we show that nuclear GAPDH is acetylated at Lys 160 by the acetyltransferase p300/CREB binding protein (CBP) through direct protein interaction, which in turn stimulates the acetylation and catalytic activity of p300/CBP. Consequently, downstream targets of p300/CBP, such as p53 (Refs 10,11,12,13,14,15), are activated and cause cell death. A dominant-negative mutant GAPDH with the substitution of Lys 160 to Arg (GAPDH-K160R) prevents activation of p300/CBP, blocks induction of apoptotic genes and decreases cell death. Our findings reveal a pathway in which NO-induced nuclear GAPDH mediates cell death through p300/CBP.
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U2 - 10.1038/ncb1747
DO - 10.1038/ncb1747
M3 - Article
C2 - 18552833
AN - SCOPUS:46649101876
SN - 1465-7392
VL - 10
SP - 866
EP - 873
JO - Nature cell biology
JF - Nature cell biology
IS - 7
ER -