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S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding.

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.

Pubmed ID: 15951807


  • Hara MR
  • Agrawal N
  • Kim SF
  • Cascio MB
  • Fujimuro M
  • Ozeki Y
  • Takahashi M
  • Cheah JH
  • Tankou SK
  • Hester LD
  • Ferris CD
  • Hayward SD
  • Snyder SH
  • Sawa A


Nature cell biology

Publication Data

July 1, 2005

Associated Grants

  • Agency: NIDA NIH HHS, Id: DA-00074
  • Agency: NIDA NIH HHS, Id: DA-00266
  • Agency: NIMH NIH HHS, Id: MH-069853

Mesh Terms

  • Animals
  • Apoptosis
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus
  • Cells, Cultured
  • Cysteine
  • Cytoplasm
  • Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
  • Humans
  • Lipopolysaccharides
  • Macrophages
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Models, Biological
  • Mutation
  • N-Methylaspartate
  • Nerve Tissue Proteins
  • Neurons
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Nitric Oxide Synthase Type II
  • Nuclear Proteins
  • Protein Binding
  • Protein Transport
  • Rats
  • S-Nitrosoglutathione
  • S-Nitrosothiols
  • Signal Transduction
  • Transfection
  • Two-Hybrid System Techniques
  • Ubiquitin
  • Ubiquitin-Protein Ligases