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. Author manuscript; available in PMC: 2014 May 22.
Published in final edited form as: Neuron. 2013 May 22;78(4):596–614. doi: 10.1016/j.neuron.2013.05.005

Figure 5. Schematic Representation of SNO-GAPDH Pathways.

Figure 5

Formation of SNO-GAPDH can trigger multiple signaling pathways leading to neurodegeneration.

Pathway 1: NO generated from nNOS, iNOS, or eNOS can S-nitrosylate GAPDH in the cytosol.

Pathway 2: S-Nitrosylation of GAPDH enhances its interaction with Siah1, a ubiquitin E3 ligase bearing a nuclear localization signal, allowing SNO-GAPDH to translocate into the nucleus.

Pathway 3: In the nucleus, Siah promotes degradation of nuclear proteins such as nuclear corepressor (NcoR).

Pathway 4: SNO-GAPDH also increases p300/CBP activity and induces downstream gene expression.

Pathway 5: SNO-GAPDH serves as a nuclear nitrosylase, producing SNO-SIRT1 and SNO—DNA-PK.

Pathway 6: The SNO-GAPDH/Siah1 complex can also facilitate nuclear translocation of mutant huntingtin (mtHtt) protein.

Pathway 7: Physiological levels of NO can S-nitrosylate GOSPEL, to form a SNO-GOSPEL/GAPDH complex, preventing the association of GAPDH and Siah 1.

Pathway 8: In addition to its nuclear function, SNO-GAPDH regulates iNOS activity as well as ribosomal protein L13a degradation.