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S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding

Nature Cell Biology volume 7, pages 665–674 (2005)Cite this article

Abstract

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) influences cytotoxicity, translocating to the nucleus during apoptosis. Here we report a signalling pathway in which nitric oxide (NO) generation that follows apoptotic stimulation elicits S-nitrosylation of GAPDH, which triggers binding to Siah1 (an E3 ubiquitin ligase), nuclear translocation and apoptosis. S-nitrosylation of GAPDH augments its binding to Siah1, whose nuclear localization signal mediates translocation of GAPDH. GAPDH stabilizes Siah1, facilitating its degradation of nuclear proteins. Activation of macrophages by endotoxin and of neurons by glutamate elicits GAPDH–Siah1 binding, nuclear translocation and apoptosis, which are prevented by NO deletion. The NO–S-nitrosylation–GAPDH–Siah1 cascade may represent an important molecular mechanism of cytotoxicity.

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Figure 1: GAPDH interacts with Siah1.
Figure 2: Nuclear translocation of GAPDH elicited by Siah1.
Figure 3: Stabilization of Siah1 protein by GAPDH.
Figure 4: NO causes nuclear accumulation of sulphonated GAPDH (sGAPDH).
Figure 5: S-nitrosylation of GAPDH enhances its binding to Siah1.
Figure 6: NO promotes translocation of GAPDH to the nucleus following Siah1 binding.
Figure 7: GAPDH–Siah1 cell death cascade in neurons.
Figure 8: Siah1's cytotoxic actions involve degradation of its nuclear substrates.

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Acknowledgements

This work was supported by USPHS grants DA-00266, Research Scientist Award DA-00074 (S.H.S.) and MH-069853 (A.S.), and grants from HDSA, HDF, NARSAD, Stanley and S-R foundations (A.S.). We thank L. Hanle, X. Luo, S. Sutcliffe, J. Park, J. Zarach and R. N. Cole for their technical assistance. We thank J. T. Issacs, C. A. Ross, T. W. Sedlak, H. R. Luo, D. Boehning, B.-I. Bae, A. Huang, A. Resnick, H. Uejima, and members of the Snyder laboratory for helpful discussion. We thank D. Dodson, A. Onda and Y. Lema for organizing the manuscript.

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  1. Christopher D. Ferris

    Present address: Mecklenberg Medical Group, 3535 Randolph Road, Charlotte, NC 28211, USA

Authors and Affiliations

  1. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA

    Makoto R. Hara, Nishant Agrawal, Sangwon F. Kim, Matthew B. Cascio, Masaaki Takahashi, Jaime H. Cheah, Stephanie K. Tankou, Lynda D. Hester, Christopher D. Ferris, Solomon H. Snyder & Akira Sawa

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

    Yuji Ozeki, Solomon H. Snyder & Akira Sawa

  3. Oncology Center, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA

    Masahiro Fujimuro & S. Diane Hayward

  4. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA

    Solomon H. Snyder

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Hara, M., Agrawal, N., Kim, S. et al. S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol 7, 665–674 (2005). https://doi.org/10.1038/ncb1268

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