STKE: NO Deadly Signal

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Science  22 Jul 2005:
Vol. 309, Issue 5734, pp. 537c
DOI: 10.1126/science.309.5734.537c

Reminiscent of mild-mannered Clark Kent, the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has an alter ego with potent and deadly effects. When translocated to the nucleus, GAPDH has been associated with transcriptional regulation, and Hara et al.present results implicating it in cell death. Screening for proteins that interact with GAPDH turned up Siah1, a ubiquitin ligase. In transfected cells, GAPDH moved to the nucleus, an effect that required the nuclear localization signal of Siah1. In human embryonic kidney cells undergoing apoptosis in response to staurosporine, GAPDH underwent modification via S-nitrosylation (a consequence of increased intracellular nitric oxide), which enhanced its association with Siah1. In a macrophage cell line undergoing apoptosis in response to lipopolysaccharide, GAPDH became S-nitrosylated and associated with endogenous Siah1, and this complex moved to the nucleus. All of these effects could be blocked by an inhibitor of the nitric oxide—generating enzyme iNOS (inducible nitric oxide synthase). Exactly how nuclear Siah1 promotes apoptosis remains to be explored, but its action appears to require its RING finger domain, indicating that Siah1-mediated ubiquitination and consequent degradation of nuclear proteins is one likely mechanism. — LBR

Nat. Cell Biol. 7, 665 (2005).

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