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

Makoto R. Hara, Nishant Agrawal, Sangwon F. Kim, Matthew B. Cascio, Masahiro Fujimuro, Yuji Ozeki, Masaaki Takahashi, Jaime H. Cheah, Stephanie K. Tankou, Lynda D. Hester, Christopher D. Ferris, S Diane Hayward, Solomon H. Snyder, Akira Sawa

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)665-674
Number of pages10
JournalNature cell biology
Issue number7
StatePublished - Jul 2005

ASJC Scopus subject areas

  • Cell Biology


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