Programmed Cell Death Across the Eukaryotic Kingdoms

EU 6th Framework STREP

Research group of Roberto Testi

Gangliosides & the regulation of PCD




Fig.: Molecular structure of frataxin  

Testi's laboratory intially showed that GD3 ganglioside, which is synthesized and accumulates following stress and death-inducing stimuli, is required in CD95- and ceramide-induced apoptosis in mammalian cells. Intracellular GD3 acts as a mediator of the apoptotic program by relocating to mitochondria and inducing the opening of the permeability transition pore complex, the collapse of transmembrane potential and the release of apoptogenic factors. Thus, activation of GD3 synthase is sufficient to trigger the apoptotic program in several cell types. The group currently focuses on mechanisms which control this pathway, and has identified four different levels of regualtion. One is represented by bcl2 family members, since high levels of bcl2 suppress GD3 synthase-induced apoptosis (Rippo et al., 2000. FASEB J 14, 2047-54). A second mechanism is represented by acetylation/de-acetylation of GD3 sialic acids by specific acetylases/acetylesterases (Malisan et al, 2002. J Exp Med 196, 1535-41). A third mechanism is mediated by calnexin, an ER chaperone that interacts with GD3 synthase and retains it in the ER, preventing GD3 relocation to the mitochondria (Tomassini et al., submitted). Finally, mitochondrial frataxin, whose defect causes Friedreich Ataxia, regulates GD3 synthase-induced mitochondrial damage and apoptosis (Ventura et al., in preparation). These mechanisms might be exploited to restrain lethal endogenous GD3 accumulation, thereby enhancing cellular survival under stress.

Relevant References

1) Barila et al. (2003) Caspase-dependent cleavage of c-Abl contributes to apoptosis. Mol Cell Biol 23, 2790-9
2) Malisan et al. (2002) Acetylation suppresses the proapoptotic activity of GD3 ganglioside. J Exp Med 196, 1535-41
3) Nicolo et al. (2001) UVB-induced apoptosis of human dendritic cells: contribution by caspase-dependent and caspase-independent pathways. Blood 97, 1803-8
4) Rippo et al. (2000) GD3 ganglioside directly targets mitochondria in a bcl-2-controlled fashion. FASEB J 14, 2047-54
5) De Maria et al. (1997) Requirement for GD3 ganglioside in CD95- and ceramide-induced apoptosis. Science 277, 1652-5

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