Article abstract
Nature Cell Biology 7, 665 - 674 (2005)
Published online: 12 June 2005 | doi:10.1038/ncb1268
S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding
Makoto R. Hara1, Nishant Agrawal1, Sangwon F. Kim1, Matthew B. Cascio1, Masahiro Fujimuro3, Yuji Ozeki2, Masaaki Takahashi1, Jaime H. Cheah1, Stephanie K. Tankou1, Lynda D. Hester1, Christopher D. Ferris1,5, S. Diane Hayward3, Solomon H. Snyder1,2,4 & Akira Sawa1,2
Abstract
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) influences cytotoxicity, translocating to the nucleus during apoptosis. Here we report a signalling pathway in which nitric oxide (NO) generation that follows apoptotic stimulation elicits S-nitrosylation of GAPDH, which triggers binding to Siah1 (an E3 ubiquitin ligase), nuclear translocation and apoptosis. S-nitrosylation of GAPDH augments its binding to Siah1, whose nuclear localization signal mediates translocation of GAPDH. GAPDH stabilizes Siah1, facilitating its degradation of nuclear proteins. Activation of macrophages by endotoxin and of neurons by glutamate elicits GAPDH–Siah1 binding, nuclear translocation and apoptosis, which are prevented by NO deletion. The NO–S-nitrosylation–GAPDH–Siah1 cascade may represent an important molecular mechanism of cytotoxicity.
- 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.
- Oncology Center, 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.
- Present address: Mecklenberg Medical Group, 3535 Randolph Road, Charlotte, NC 28211, USA.
Correspondence to: Solomon H. Snyder1,2,4 e-mail: ssnyder@jhmi.edu
Correspondence to: Akira Sawa1,2 e-mail: asawa1@jhmi.edu
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