Advertisement

Cellular and Molecular Neurobiology

, Volume 26, Issue 4–6, pp 525–536 | Cite as

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

  • Makoto R. Hara
  • Solomon H. SnyderEmail author
Article

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.

KEY WORDS:

GAPDH nitric oxide nitric oxide synthase S-nitrosylation siah apoptosis parkinson's disease huntington's disease 

Notes

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.

REFERENCES

  1. Bae, B. I., Xu, H., Igarashi, S., Fujimuro, M., Agrawal, N., Taya, Y., Hayward, S. D., Moran, T. H., Montell, C., Ross, C. A., Snyder, S. H., and Sawa, A. (2005). p53 mediates cellular dysfunction and behavioral abnormalities in Huntington's disease. Neuron 47:29–41.PubMedCrossRefGoogle Scholar
  2. Bae, B. I., Hara, M. R., Cascio, M. B., Wellington, C. L., Hayden, M. R., Ross, C. A., Ha, H. C., Li, X. J., Snyder, S. H., and Sawa, A. (2006). Mutant Huntingtin: Nuclear translocation and cytotoxicity mediated by GAPDH. Proc. Natl. Acad. Sci. U.S.A. 103:3405–3409.Google Scholar
  3. Birkmayer, W., Knoll, J., Riederer, P., Youdim, M. B., Hars, V., and Marton, J. (1985). Increased life expectancy resulting from addition of l-deprenyl to Madopar treatment in Parkinson's disease: A longterm study. J. Neural. Transm. 64:113–127.PubMedCrossRefGoogle Scholar
  4. Boehning, D., Patterson, R. L., Sedaghat, L., Glebova, N. O., Kurosaki, T., and Snyder, S. H. (2003). Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nat. Cell. Biol. 5:1051–1061.PubMedCrossRefGoogle Scholar
  5. Brown, V. M., Krynetski, E. Y., Krynetskaia, N. F., Grieger, D., Mukatira, S. T., Murti, K. G., Slaughter, C. A., Park, H. W., and Evans, W. E. (2004). A novel CRM1-mediated nuclear export signal governs nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase following genotoxic stress. J. Biol. Chem. 279:5984–5992.PubMedCrossRefGoogle Scholar
  6. Brune, B., and Lapetina, E. G. (1989). Activation of a cytosolic ADP-ribosyltransferase by nitric oxide-generating agents. J. Biol. Chem. 264:8455–8458.PubMedGoogle Scholar
  7. Burke, J. R., Enghild, J. J., Martin, M. E., Jou, Y. S., Myers, R. M., Roses, A. D., Vance, J. M., and Strittmatter, W. J. (1996). Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nat. Med. 2:347–350.PubMedCrossRefGoogle Scholar
  8. Chen, M., Ona, V. O., Li, M., Ferrante, R. J., Fink, K. B., Zhu, S., Bian, J., Guo, L., Farrell, L. A., Hersch, S. M., Hobbs, W., Vonsattel, J. P., Cha, J. H., and Friedlander, R. M. (2000). Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat. Med. 6:797–801.PubMedCrossRefGoogle Scholar
  9. Dawson, V. L., Dawson, T. M., Bartley, D. A., Uhl, G. R., and Snyder, S. H. (1993). Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures. J. Neurosci. 13:2651–2661.PubMedGoogle Scholar
  10. Dawson, V. L., Dawson, T. M., London, E. D., Bredt, D. S., and Snyder, S. H. (1991). Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc. Natl. Acad. Sci. U.S.A. 88:6368–6371.PubMedCrossRefGoogle Scholar
  11. Della, N. G., Senior, P. V., and Bowtell, D. D. (1993). Isolation and characterisation of murine homologues of the Drosophila seven in absentia gene (sina). Development 117:1333–1343.PubMedGoogle Scholar
  12. Fiucci, G., Beaucourt, S., Duflaut, D., Lespagnol, A., Stumptner-Cuvelette, P., Geant, A., Buchwalter, G., Tuynder, M., Susini, L., Lassalle, J. M., Wasylyk, C., Wasylyk, B., Oren, M., Amson, R., and Telerman, A. (2004). Siah-1b is a direct transcriptional target of p53: Identification of the functional p53 responsive element in the siah-1b promoter. Proc. Natl. Acad. Sci. U.S.A. 101:3510–3515.PubMedCrossRefGoogle Scholar
  13. Fukushima, T., Zapata, J. M., Singha, N. C., Thomas, M., Kress, C. L., Krajewska, M., Krajewski, S., Ronai, Z., Reed, J. C., and Matsuzawa, S. (2006). Critical function for SIP, a ubiquitin E3 ligase component of the beta-catenin degradation pathway, for thymocyte development and G1 checkpoint. Immunity 24:29–39.PubMedCrossRefGoogle Scholar
  14. Graven, K. K., Troxler, R. F., Kornfeld, H., Panchenko, M. V., and Farber, H. W. (1994). Regulation of endothelial cell glyceraldehyde-3-phosphate dehydrogenase expression by hypoxia. J. Biol. Chem. 269:24446–24453.PubMedGoogle Scholar
  15. Hantraye, P., Brouillet, E., Ferrante, R., Palfi, S., Dolan, R., Matthews, R. T., and Beal, M. F. (1996). Inhibition of neuronal nitric oxide synthase prevents MPTP-induced parkinsonism in baboons. Nat. Med. 2:1017–1021.PubMedCrossRefGoogle Scholar
  16. Hara, M. R., Agrawal, N., Kim, S. F., Cascio, M. B., Fujimuro, M., Ozeki, Y., Takahashi, M., Cheah, J. H., Tankou, S. K., Hester, L. D., Ferris, C. D., Hayward, S. D., Snyder, S. H., and Sawa, A. (2005). S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat. Cell. Biol. 7:665–674.PubMedCrossRefGoogle Scholar
  17. Hara, M. R., Thomas, B., Cascio, M. B., Bae, B. I., Hester, L. D., Dawson, V. L., Dawson, T. M., Sawa, A., and Snyder, S. H. (2006). Neuroprotection by pharmacologic blockade of the GAPDH death cascade. Proc. Natl. Acad. Sci. U.S.A. 103:3887–3889.Google Scholar
  18. Hu, G., and Fearon, E. R. (1999). Siah-1 N-terminal RING domain is required for proteolysis function, and C-terminal sequences regulate oligomerization and binding to target proteins. Mol. Cell. Biol. 19:724–732.PubMedGoogle Scholar
  19. Ignarro, L. J. (1990). Haem-dependent activation of guanylate cyclase and cyclic GMP formation by endogenous nitric oxide: A unique transduction mechanism for transcellular signaling. Pharmacol. Toxicol. 67:1–7.PubMedCrossRefGoogle Scholar
  20. Ishitani, R., and Chuang, D. M. (1996). Glyceraldehyde-3-phosphate dehydrogenase antisense oligodeoxynucleotides protect against cytosine arabinonucleoside-induced apoptosis in cultured cerebellar neurons. Proc. Natl. Acad. Sci. U.S.A. 93:9937–9941.PubMedCrossRefGoogle Scholar
  21. Ishitani, R., Kimura, M., Sunaga, K., Katsube, N., Tanaka, M., and Chuang, D. M. (1996a). An antisense oligodeoxynucleotide to glyceraldehyde-3-phosphate dehydrogenase blocks age-induced apoptosis of mature cerebrocortical neurons in culture. J. Pharmacol. Exp. Ther. 278:447–454.PubMedGoogle Scholar
  22. Ishitani, R., Sunaga, K., Hirano, A., Saunders, P., Katsube, N., and Chuang, D. M. (1996b). Evidence that glyceraldehyde-3-phosphate dehydrogenase is involved in age-induced apoptosis in mature cerebellar neurons in culture. J. Neurochem. 66:928–935.PubMedCrossRefGoogle Scholar
  23. Jaffrey, S. R., Erdjument-Bromage, H., Ferris, C. D., Tempst, P., and Snyder, S. H. (2001). Protein S-nitrosylation: A physiological signal for neuronal nitric oxide. Nat. Cell. Biol. 3:193–197.PubMedCrossRefGoogle Scholar
  24. Jenner, P. (2004). Preclinical evidence for neuroprotection with monoamine oxidase-B inhibitors in Parkinson's disease. Neurology 63:S13– S22.PubMedCrossRefGoogle Scholar
  25. Koshy, B., Matilla, T., Burright, E. N., Merry, D. E., Fischbeck, K. H., Orr, H. T., and Zoghbi, H. Y. (1996). Spinocerebellar ataxia type-1 and spinobulbar muscular atrophy gene products interact with glyceraldehyde-3-phosphate dehydrogenase. Hum. Mol. Genet. 5:1311–1318.PubMedCrossRefGoogle Scholar
  26. Kragten, E., Lalande, I., Zimmermann, K., Roggo, S., Schindler, P., Muller, D., van Oostrum, J., Waldmeier, P., and Furst, P. (1998). Glyceraldehyde-3-phosphate dehydrogenase, the putative target of the antiapoptotic compounds CGP 3466 and R-(−)-deprenyl. J. Biol. Chem. 273:5821–5828.PubMedCrossRefGoogle Scholar
  27. Kudo, N., Matsumori, N., Taoka, H., Fujiwara, D., Schreiner, E. P., Wolff, B., Yoshida, M., and Horinouchi, S. (1999). Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region. Proc. Natl. Acad. Sci. U.S.A. 96:9112–9117.PubMedCrossRefGoogle Scholar
  28. Liani, E., Eyal, A., Avraham, E., Shemer, R., Szargel, R., Berg, D., Bornemann, A., Riess, O., Ross, C. A., Rott, R., and Engelender, S. (2004). Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease. Proc. Natl. Acad. Sci. U.S.A. 101:5500–5505.PubMedCrossRefGoogle Scholar
  29. Liberatore, G. T., Jackson-Lewis, V., Vukosavic, S., Mandir, A. S., Vila, M., McAuliffe, W. G., Dawson, V. L., Dawson, T. M., and Przedborski, S. (1999). Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat. Med. 5:1403–1409.PubMedCrossRefGoogle Scholar
  30. Matsuzawa, S. I., and Reed, J. C. (2001). Siah-1, SIP, and Ebi collaborate in a novel pathway for beta-catenin degradation linked to p53 responses. Mol. Cell. 7:915–926.PubMedCrossRefGoogle Scholar
  31. McDonald, L. J., and Moss, J. (1993). Stimulation by nitric oxide of an NAD linkage to glyceraldehyde-3-phosphate dehydrogenase. Proc. Natl. Acad. Sci. U.S.A. 90:6238–6241.PubMedCrossRefGoogle Scholar
  32. Meyer-Siegler, K., Mauro, D. J., Seal, G., Wurzer, J., deRiel, J. K., and Sirover, M. A. (1991). A human nuclear uracil DNA glycosylase is the 37-kDa subunit of glyceraldehyde-3-phosphate dehydrogenase. Proc. Natl. Acad. Sci. U.S.A. 88:8460–8464.PubMedCrossRefGoogle Scholar
  33. Mohr, S., Stamler, J. S., and Brune, B. (1996). Posttranslational modification of glyceraldehyde-3-phosphate dehydrogenase by S-nitrosylation and subsequent NADH attachment. J. Biol. Chem. 271:4209–4214.PubMedCrossRefGoogle Scholar
  34. Morgenegg, G., Winkler, G. C., Hubscher, U., Heizmann, C. W., Mous, J., and Kuenzle, C. C. (1986). Glyceraldehyde-3-phosphate dehydrogenase is a nonhistone protein and a possible activator of transcription in neurons. J. Neurochem. 47:54–62.PubMedCrossRefGoogle Scholar
  35. Moriyoshi, K., Iijima, K., Fujii, H., Ito, H., Cho, Y., and Nakanishi, S. (2004). Seven in absentia homolog 1A mediates ubiquitination and degradation of group 1 metabotropic glutamate receptors. Proc. Natl. Acad. Sci. U.S.A. 101:8614–8619.PubMedCrossRefGoogle Scholar
  36. Nagano, Y., Yamashita, H., Takahashi, T., Kishida, S., Nakamura, T., Iseki, E., Hattori, N., Mizuno, Y., Kikuchi, A., and Matsumoto, M. (2003). Siah-1 facilitates ubiquitination and degradation of synphilin-1. J. Biol. Chem. 278:51504–51514.PubMedCrossRefGoogle Scholar
  37. Nagata, E., Luo, H. R., Saiardi, A., Bae, B, I., Suzuki, N., and Snyder, S. H. (2005). Inositol hexakisphosphate kinase-2, a physiologic mediator of cell death. J. Biol. Chem. 280:1634–1640.PubMedCrossRefGoogle Scholar
  38. Patterson, R. L., van Rossum, D. B., Kaplin, A. I., Barrow, R. K., and Snyder, S. H. (2005). Inositol 1,4,5-trisphosphate receptor/GAPDH complex augments Ca2+ release via locally derived NADH. Proc. Natl. Acad. Sci. U.S.A. 102:1357–1359.PubMedCrossRefGoogle Scholar
  39. Przedborski, S., Jackson-Lewis, V., Yokoyama, R., Shibata, T., Dawson, V. L., and Dawson, T. M. (1996). Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Proc. Natl. Acad. Sci. U.S.A. 93:4565–4571.PubMedCrossRefGoogle Scholar
  40. Sawa, A., Khan, A. A., Hester, L. D., and Snyder, S. H. (1997). Glyceraldehyde-3-phosphate dehydrogenase: Nuclear translocation participates in neuronal and nonneuronal cell death. Proc. Natl. Acad. Sci. U.S.A. 94:11669–11674.PubMedCrossRefGoogle Scholar
  41. Sawa, A., Wiegand, G. W., Cooper, J., Margolis, R. L., Sharp, A. H., Lawler, J. F.Jr., Greenamyre, J. T., Snyder, S. H., and Ross, C. A. (1999). Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization. Nat. Med. 5:1194–1198.PubMedCrossRefGoogle Scholar
  42. Senatorov, V. V., Charles, V., Reddy, P. H., Tagle, D. A., and Chuang, D. M. (2003). Overexpression and nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase in a transgenic mouse model of Huntington's disease. Mol. Cell. Neurosci. 22:285–297.PubMedCrossRefGoogle Scholar
  43. Sharpless, N. E., and DePinho, R. A. (2002). p53: Good cop/bad cop. Cell 110:9–12.PubMedCrossRefGoogle Scholar
  44. Singh, R., and Green, M. R. (1993). Sequence-specific binding of transfer RNA by glyceraldehyde-3-phosphate dehydrogenase. Science 259:365–368.PubMedCrossRefGoogle Scholar
  45. Sourisseau, T., Desbois, C., Debure, L., Bowtell, D. D., Cato, A. C., Schneikert, J., Moyse, E., and Michel, D. (2001). Alteration of the stability of Bag-1 protein in the control of olfactory neuronal apoptosis. J. Cell. Sci. 114:1409–1416.PubMedGoogle Scholar
  46. Sundararaj, K. P., Wood, R. E., Ponnusamy, S., Salas, A. M., Szulc, Z., Bielawska, A., Obeid, L. M., Hannun, Y. A., and Ogretmen, B. (2004). Rapid shortening of telomere length in response to ceramide involves the inhibition of telomere binding activity of nuclear glyceraldehyde-3-phosphate dehydrogenase. J. Biol. Chem. 279:6152–6162.PubMedCrossRefGoogle Scholar
  47. Tatton, N. A. (2000). Increased caspase 3 and Bax immunoreactivity accompany nuclear GAPDH translocation and neuronal apoptosis in Parkinson's disease. Exp. Neurol. 166:29–43.PubMedCrossRefGoogle Scholar
  48. Tokunaga, K., Nakamura. Y., Sakata, K., Fujimori, K., Ohkubo, M., Sawada, K., and Sakiyama, S. (1987). Enhanced expression of a glyceraldehyde-3-phosphate dehydrogenase gene in human lung cancers. Cancer Res. 47:5616–5619.PubMedGoogle Scholar
  49. Vogelstein, B., Lane, D., and Levine, A. J. (2000). Surfing the p53 network. Nature 408:307–310.PubMedCrossRefGoogle Scholar
  50. Waldmeier, P. C., Boulton, A. A., Cools, A. R., Kato, A. C., and Tatton, W. G. (2000). Neurorescuing effects of the GAPDH ligand CGP 3466B. J. Neural. Transm. Suppl. 60:197–214.Google Scholar
  51. Yamaji, R., Fujita, K., Takahashi, S., Yoneda, H., Nagao, K., Masuda, W., Naito, M., Tsuruo, T., Miyatake, K., Inui, H., and Nakano, Y. (2003). Hypoxia up-regulates glyceraldehyde-3-phosphate dehydrogenase in mouse brain capillary endothelial cells: involvement of Na+/Ca2+ exchanger. Biochim. Biophys. Acta 1593:269–276.PubMedCrossRefGoogle Scholar
  52. Zhang, J., and Snyder, S. H. (1992). Nitric oxide stimulates auto-ADP-ribosylation of glyceraldehyde-3-phosphate dehydrogenase. Proc. Natl. Acad. Sci. U.S.A. 89:9382–9385.PubMedCrossRefGoogle Scholar
  53. Zheng, L., Roeder, R. G., and Luo, Y. (2003). S phase activation of the histone H2B promoter by OCA-S, a coactivator complex that contains GAPDH as a key component. Cell 114:255–266.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  1. 1.The Solomon H. Snyder Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Psychiatry and Behavioral SciencesJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations