S-nitrosylation of B23/nucleophosmin by GAPDH protects cells from the SIAH1–GAPDH death cascade

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.