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Nitric Oxide–GAPDH–Siah: A Novel Cell Death Cascade

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Summary

1. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an extremely abundant glycolytic enzyme, and exemplifies the class of proteins with multiple, seemingly unrelated functions. Recent studies indicate that it is a major intracellular messenger mediating apoptotic cell death. This paper reviews the GAPDH cell death cascade and discusses its clinical relevance.

2. A wide range of apoptotic stimuli activate NO formation, which S-nitrosylates GAPDH. The S-nitrosylation abolishes catalytic activity and confers upon GAPDH the ability to bind to Siah, an E3-ubiquitin-ligase, which translocates GAPDH to the nucleus. In the nucleus, GAPDH stabilizes the rapidly turning over Siah, enabling it to degrade selected target proteins and affect apoptosis.

3. The cytotoxicity of mutant Huntingtin (mHtt) requires nuclear translocation which appears to be mediated via a ternary complex of GAPDH—Siah—mHtt. The neuroprotective actions of the monoamine oxidase inhibitor R-(—)-deprenyl (deprenyl) reflect blockade of GAPDH—Siah binding. Thus, novel cytoprotective therapies may emerge from agents that prevent GAPDH—Siah binding.

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ACKNOWLEDGMENTS

This work was supported by USPHS grants DA-00266 and Research Scientist AwardDA00074 (SHS). We thank Dr. Akira Sawa, Dr. Byoung-Il Bae, and Matthew B. Cascio for their helpful comments. We thank Dr. Peter Waldmeier for providing us TCH346.

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  1. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Makoto R. Hara & Solomon H. Snyder

  2. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Solomon H. Snyder

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Hara, M.R., Snyder, S.H. Nitric Oxide–GAPDH–Siah: A Novel Cell Death Cascade. Cell Mol Neurobiol 26, 525–536 (2006). https://doi.org/10.1007/s10571-006-9011-6

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