title: S-nitrosylation of B23/nucleophosmin by GAPDH protects cells from the SIAH1-GAPDH death cascade.
abstract: B23/nucleophosmin is a multifunctional protein that participates in cell survival signaling by shuttling between the nucleolus/nucleoplasm and nucleus/cytoplasm. In this paper, we report a novel neuroprotective function of B23 through regulation of the SIAH1-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) death cascade. B23 physiologically bound to both SIAH1 and GAPDH, disrupting the SIAH1-GAPDH complex in the nucleus in response to nitrosative stress. S-nitrosylation of B23 at cysteine 275 by trans-nitrosylation from GAPDH dramatically reduced the interaction between SIAH1 and GAPDH. S-nitrosylation of B23 enhanced B23-SIAH1 binding and mediated the neuroprotective actions of B23 by abrogating the E3 ligase activity of SIAH1. In mice, overexpression of B23 notably inhibited N-methyl-d-aspartate-mediated neurotoxicity, whereas expression of the C275S mutant, which is defective in binding to SIAH1, did not prevent neurotoxicity. Thus, B23 regulates neuronal survival by preventing SIAH1-GAPDH death signaling under stress-induced conditions in the brain.
authors.affiliation: Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.
authors.forename: Sang Bae
authors.initials: SB
authors.lastname: Lee
authors.forename: Chung Kwon
authors.initials: CK
authors.lastname: Kim
authors.forename: Kyung-Hoon
authors.initials: KH
authors.lastname: Lee
authors.forename: Jee-Yin
authors.initials: JY
authors.lastname: Ahn
mesh_terms: D000818:Animals; D016923:Cell Death; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry* / Q000378:metabolism*; D000090243:Nucleophosmin; D016716:PC12 Cells; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
chemical_list: D009603:Nitroso Compounds; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D011506:Proteins; D000090243:Nucleophosmin; D016202:N-Methylaspartate; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; C484442:Siah1a protein, mouse; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins