Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis

Nilkantha Sen, Makoto R. Hara, Michael D. Kornberg, Matthew B. Cascio, Byoung Il Bae, Neelam Shahani, Bobby Thomas, Ted M. Dawson, Valina L. Dawson, Solomon H. Snyder, Akira Sawa

Research output: Contribution to journalArticle

266 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)866-873
Number of pages8
JournalNature Cell Biology
Volume10
Issue number7
DOIs
StatePublished - Jul 1 2008

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CREB-Binding Protein
Glyceraldehyde-3-Phosphate Dehydrogenases
Nitric Oxide
Apoptosis
Cell Death
Nuclear Localization Signals
Ubiquitin-Protein Ligases
Nitric Oxide Synthase Type II
Glycolysis
Acetylation
Cause of Death
Proteins

ASJC Scopus subject areas

  • Cell Biology

Cite this

Sen, N., Hara, M. R., Kornberg, M. D., Cascio, M. B., Bae, B. I., Shahani, N., ... Sawa, A. (2008). Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nature Cell Biology, 10(7), 866-873. https://doi.org/10.1038/ncb1747

Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. / Sen, Nilkantha; Hara, Makoto R.; Kornberg, Michael D.; Cascio, Matthew B.; Bae, Byoung Il; Shahani, Neelam; Thomas, Bobby; Dawson, Ted M.; Dawson, Valina L.; Snyder, Solomon H.; Sawa, Akira.

In: Nature Cell Biology, Vol. 10, No. 7, 01.07.2008, p. 866-873.

Research output: Contribution to journalArticle

Sen, N, Hara, MR, Kornberg, MD, Cascio, MB, Bae, BI, Shahani, N, Thomas, B, Dawson, TM, Dawson, VL, Snyder, SH & Sawa, A 2008, 'Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis', Nature Cell Biology, vol. 10, no. 7, pp. 866-873. https://doi.org/10.1038/ncb1747
Sen N, Hara MR, Kornberg MD, Cascio MB, Bae BI, Shahani N et al. Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nature Cell Biology. 2008 Jul 1;10(7):866-873. https://doi.org/10.1038/ncb1747
Sen, Nilkantha ; Hara, Makoto R. ; Kornberg, Michael D. ; Cascio, Matthew B. ; Bae, Byoung Il ; Shahani, Neelam ; Thomas, Bobby ; Dawson, Ted M. ; Dawson, Valina L. ; Snyder, Solomon H. ; Sawa, Akira. / Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. In: Nature Cell Biology. 2008 ; Vol. 10, No. 7. pp. 866-873.
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