GAPDH as a sensor of NO stress.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a classic glycolytic enzyme, and accumulating evidence has suggested that GAPDH is a multi-functional protein. In particular, its role as a mediator for cell death has been highlighted. For the last decade, many groups reported that a pool of GAPDH translocates to the nucleus under a variety of stressors, most of which are associated with oxidative stress. At the molecular level, sequential steps lead to nuclear translocation of GAPDH during cell death as follows: first, a catalytic cysteine in GAPDH (C150 in rat GAPDH) is S-nitrosylated by nitric oxide (NO) that is generated from inducible nitric oxide synthase (iNOS) and/or neuronal NOS (nNOS); second, the modified GAPDH becomes capable of binding with Siah1, an E3 ubiquitin ligase, and stabilizes it; third, the GAPDH-Siah protein complex translocates to the nucleus, dependent on Siah1's nuclear localization signal, and degrades Siah1's substrates in the nucleus, which results in cytotoxicity. A recent report suggests that GAPDH may be genetically associated with late-onset of Alzheimer's disease. (-)-deprenyl, which has originally been used as a monoamine oxidase inhibitor for Parkinson's disease, binds to GAPDH and displays neuroprotective actions, but its molecular mechanism is still unclear. The NO/GAPDH/Siah1 death cascade will contribute to the molecular understanding of a role of GAPDH in neurodegenerative disorders and help to establish novel therapeutic strategies.
Department of Neuroscience, Johns Hopkins University School of Medicine, 600 North Wolfe street, Baltimore, MD 21287, USA.
Makoto R
MR
Hara
Matthew B
MB
Cascio
Akira
A
Sawa
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism*; D006801:Humans; D009410:Nerve Degeneration; D009569:Nitric Oxide / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism
D009687:Nuclear Proteins; D009569:Nitric Oxide; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases