Letter abstract
Nature Cell Biology 10, 866 - 873 (2008)
Published online: 15 June 2008 | doi:10.1038/ncb1747
Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis
Nilkantha Sen1,9, Makoto R. Hara1,7,8,9, Michael D. Kornberg1, Matthew B. Cascio1, Byoung-Il Bae1, Neelam Shahani2, Bobby Thomas3,6, Ted M. Dawson1,3,6,7, Valina L. Dawson1,3,4,6,7, Solomon H. Snyder1,2,5,7 & Akira Sawa1,2,7
Besides its role in glycolysis, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) initiates a cell death cascade1, 2, 3, 4, 5, 6, 7, 8, 9. 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.
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
- Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
- Department of Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
- Department of Graduate Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
- Current address: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
- These authors contributed equally to this work.
Correspondence to: Akira Sawa1,2,7 e-mail: asawa1@jhmi.edu
Correspondence to: Solomon H. Snyder1,2,5,7 e-mail: ssnyder@jhmi.edu
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