Dynamics of lipid raft components during lymphocyte apoptosis: The paradigmatic role of GD3

Abstract

Several investigations have been carried out since many years in order to precisely address the function of lipid rafts in cell life and death. On the basis of the biochemical nature of lipid rafts, composed by sphingolipids, including gangliosides, sphingomyelin, cholesterol and signaling proteins, a plethora of possible interactions with various subcellular structures has been suggested. Their structural and functional role at the plasma membrane as well as in cell organelles such as endoplasmic reticulum and Golgi apparatus has been analyzed in detail in several studies. In particular, a specific activity of lipid rafts has been hypothesized to contribute to cell death by apoptosis. Although detected in various cell types, the role of lipid rafts in apoptosis has however been mostly studied in lymphocytes where the physiological apoptotic program occurs after CD95/Fas triggering. In this review, the possible contribution of lipid rafts to the cascade of events leading to T cell apoptosis after CD95/Fas ligation are summarized. Particular attention has been given to the mitochondrial raft-like microdomains, which may represent preferential sites where some key reactions can take place and can be catalyzed, leading to either survival or death of T cells.

Ganglioside accumulation in activated glia in the developing brain: comparison between WT and GalNAcT KO mice

“…The present experiments showing that ethanol still induced robust neurodegeneration in KO mice ( Fig. 3 ) favor the putative importance of GD3 over GM2 in mitochondria-mediated apoptosis in GalNAcT KO mice, in line with a reported role for GD3 in CD95/Fas-mediated apoptosis in lymphocytes ( 21 ). It is also possible that the lack of neuroprotective GM1 ganglioside in KO mice rendered neurons more vulnerable to apoptotic stimuli, as shown in previous studies (67)(68)(69).…”

“…Previously, we proposed that GM2 found in mitochondria in WT brain exposed to ethanol plays a role in neurodegenerative processes, because GM2, as well as GD3, enhanced cytochrome c release from isolated mitochondria ( 16,21 ). The present experiments showing that ethanol still induced robust neurodegeneration in KO mice ( Fig.…”

“…The fi xed brains or hemispheres were transferred to phosphate-buffered saline solution and kept at 4°C for 2-5 days until cutting 50 m-thick vibratome sections. The free-fl oating sections were immunostained using anti-GM2 antibody (a mouse detected in mitochondria and lysosomes in neurons, and GM2, as well as GD3 ganglioside, enhances cytochrome c release from isolated mitochondria ( 16 ), suggesting that GM2 may be involved in mitochondria-mediated apoptosis, as indicated for GD3 in CD95/Fas-mediated apoptosis in lymphocytes ( 21 ).…”

p56Lck Tyrosine Kinase Enhances the Assembly of Death-inducing Signaling Complex during Fas-mediated Apoptosis

“…Cholesterol and sphingolipid-enriched rafts, also called detergent-resistant membranes, have been proposed as platforms for compartmentalizing dynamically regulated Fas signaling complexes at the plasma membrane (16, 22, 59 -61). Although detected in various cell types, the role of lipid rafts in apoptosis has, however, been mostly studied in lymphocytes where the physiological apoptotic program occurs after Fas receptor triggering using conventional Triton X-soluble and -insoluble fractions isolated by sucrose gradient (15)(16)(17)(18)(19)(20)(21)(22). The cells stimulated to undergo apoptosis appear to use membrane rafts in the death-signaling process by mobilization of rafts to localized regions of the membrane that are now enriched with apoptotic signaling effectors.…”

“…Although the DISC is rapidly assembled, several lines of evidence suggest that formation of this complex is not the first consequence of Fas stimulation but rather a later step in the conversion of signaling "inefficient" Fas complexes into "activated" receptor complexes (11,12). In particular, formation of Fas microclusters (12) and high stability supramolecular clusters via receptor palmitoylation (13, 14), actin reorganization (12), inducible or constitutive association with detergent-resistant microdomains known as lipid rafts (15)(16)(17)(18)(19)(20)(21)(22), and the production of acid sphingomyelinase-mediated ceramide (11) have been proposed as important intermediate steps preceding robust DISC formation.These studies clearly suggest that Fas-induced apoptosis can be controlled at the level of the cytoplasmic membrane. Although specific interactions between Fas, FADD, and procaspase-8/10 via their death domains and death effector domains are well documented, little is known about the mechanism(s) that regulates the recruitment of these proteins to CD95 after anti-Fas treatment.…”