Nitric oxide-GAPDH-Siah: a novel cell death cascade.

Area of Science:

• Biochemistry
• Cell Biology
• Neuroscience

Background:

• Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a glycolytic enzyme with diverse functions.
• Recent evidence highlights GAPDH's role as an intracellular messenger in apoptotic cell death.
• Understanding GAPDH's non-glycolytic functions is crucial for cell death research.

Purpose of the Study:

• To review the Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) cell death cascade.
• To discuss the clinical relevance of GAPDH in apoptosis.
• To explore potential therapeutic strategies targeting the GAPDH pathway.

Main Methods:

• Investigated the role of nitric oxide (NO) in activating GAPDH.
• Examined the interaction between S-nitrosylated GAPDH and Siah, an E3-ubiquitin ligase.
• Analyzed the nuclear translocation of GAPDH and its role in protein degradation.

Main Results:

• Apoptotic stimuli induce NO formation, leading to GAPDH S-nitrosylation.
• S-nitrosylated GAPDH binds to Siah, facilitating nuclear translocation.
• GAPDH stabilizes Siah in the nucleus, promoting the degradation of target proteins and apoptosis.
• The GAPDH-Siah complex mediates the nuclear translocation of mutant Huntingtin (mHtt).

Conclusions:

• GAPDH is a critical mediator of the apoptotic cell death cascade.
• The interaction between GAPDH and Siah is a key step in nuclear translocation and apoptosis.
• Blocking GAPDH-Siah binding, as with R-(-)-deprenyl, shows neuroprotective potential.
• Targeting the GAPDH-Siah interaction may lead to novel cytoprotective therapies.