An essential role for membrane rafts in the initiation of Fas/CD95‐triggered cell death in mouse thymocytes

Hueber, Anne-Odile; Bernard, Anne‐Marie; Hérincs, Zoltán; Couzinet, Arnaud; He, Hai-Tao

doi:10.1093/embo-reports/kvf022

Cited by 209 publications

(189 citation statements)

References 28 publications

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“…Most of these studies suggested that the formation of ceramide-enriched membrane platforms is initiated within small cholesterol-and sphingolipid-enriched membrane rafts. The notion that rafts are important for the induction of apoptosis is supported by several recent studies demonstrating that destruction of these membrane rafts prevents CD95 clustering, recruitment of FADD and caspase 8 and apoptosis by CD95 (Cremesti et al, 2001;Grassme et al, 2001b;Hueber et al, 2002;Scheel-Toellner et al, 2002). However, our studies go far beyond the finding that rafts are involved in apoptosis and suggest a mechanism how small rafts in resting cells can be transformed into a signaling unit that transmits signals from out to inside of the cell.…”

Section: Discussionsupporting

confidence: 72%

“…Rafts are organized membrane domains mainly composed of glycosphingolipids, sphingomyelin, cholesterol and specific membrane proteins (Simons and Ikonen, 1997;Brown and London, 1998). Several studies indicated that rafts are required to cluster CD95 and to recruit FADD, caspase 8 and 3 to CD95 upon stimulation (Grassme et al, 2001bHueber et al, 2002;Scheel-Toellner et al, 2002;Delmas et al, 2003;Aouad et al, 2004;Eramo et al, 2004). Accordingly, disruption of rafts prevented CD95-induced apoptosis, at least in most cells (Grassme et al, 2001b;Cremesti et al, 2001;Hueber et al, 2002;Scheel-Toellner et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

2006

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We have previously shown that activation of the acid sphingomyelinase (ASM), the release of ceramide and the formation of ceramide-enriched membrane domains are central for the induction of apoptosis by CD95. Here, we demonstrate that tumor necrosis factor-related apoptosisinducing ligand (TRAIL) and CD95 activate the ASM via a redox mechanism resulting in release of ceramide and formation of ceramide-enriched membrane platforms. Ceramide-enriched membrane platforms serve to cluster DR5 upon stimulation. Antioxidants prevent TRAILmediated stimulation of ASM, the release of ceramide, the formation of ceramide-enriched membrane platforms and the induction of apoptosis by TRAIL. Further, ASMdeficient splenocytes fail to cluster DR5 in ceramideenriched membrane domains upon TRAIL stimulation and resist TRAIL-induced apoptosis, events that were restored by addition of natural C 16 -ceramide. A dose-response analysis indicates that ceramide-enriched membrane platforms greatly sensitized tumor cells to TRAIL-induced apoptosis. Our data indicate that ceramide-enriched membrane platforms are required for the signaling of TRAIL-DR5 complexes under physiological conditions.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

2006

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“…8,17 Biochemically, these nanodomains can be isolated from cell lysate thanks to their insolubility in non-ionic detergent, and known as detergentresistant membrane nanodomains (DRMs). We subjected SW480 Fas WT cells to DRM isolation and showed that 27% of Fas is located in the DRM fractions, whereas only 14% when DHHC7 is knocked down (Figure 3d), validating by a genetic approach that DHHC7 is allowing Fas to be targeted to specific membrane nanodomains probably by palmitoylation.…”

Section: Resultsmentioning

confidence: 99%

“…8,9 At the molecular level, we and others already reported that the pro-death role of Fas palmitoylation relies on (i) the formation of supramolecular Fas aggregates 9 and (ii) Fas targeting in nanodomains enriched in cholesterol and glycosphingolipids, which is a prerequisite for proper activation of Fas-induced cell death. 8,[17][18][19][20][21] In these domains and upon FasL binding, palmitoylation allows Fas to recruit ezrin and actin cytoskeleton that lead to Fas internalization and transmission of death signal. 8 We thus aimed at understanding how Fas palmitoylation is regulated.…”

mentioning

confidence: 99%

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

et al. 2014

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The death receptor Fas undergoes a variety of post-translational modifications including S-palmitoylation. This protein acylation has been reported essential for an optimal cell death signaling by allowing both a proper Fas localization in cholesterol and sphingolipid-enriched membrane nanodomains, as well as Fas high-molecular weight complexes. In human, S-palmitoylation is controlled by 23 members of the DHHC family through their palmitoyl acyltransferase activity. In order to better understand the role of this post-translational modification in the regulation of the Fas-mediated apoptosis pathway, we performed a screen that allowed the identification of DHHC7 as a Fas-palmitoylating enzyme. Indeed, modifying DHHC7 expression by specific silencing or overexpression, respectively, reduces or enhances Fas palmitoylation and DHHC7 co-immunoprecipitates with Fas. At a functional level, DHHC7-mediated palmitoylation of Fas allows a proper Fas expression level by preventing its degradation through the lysosomes. Indeed, the decrease of Fas expression obtained upon loss of Fas palmitoylation can be restored by inhibiting the lysosomal degradation pathway. We describe the modification of Fas by palmitoylation as a novel mechanism for the regulation of Fas expression through its ability to circumvent its degradation by lysosomal proteolysis. Cell Death and Differentiation (2015) We demonstrated that Fas and FasL are constitutively modified by S-palmitoylation, a reversible post-translational modification that consists in the addition of a palmitic acid on the cysteine residue through a thiol linkage. [8][9][10] The palmitoylation of a protein can affect its interactions with its surrounding membrane lipids and proteins, therefore impacting certain properties such as association with specific membrane domains, trafficking between cell compartments or stability. [11][12][13] The palmitoylation reaction is catalyzed by the conserved DHHC (aspartate-histidine-histidine-cysteine) family of enzymes, which are characterized by the specific DHHC motif required for the palmitoyl acyltransferase (PAT) activity. 14 In human, the 23 members of the DHHC family described are localized to the distinct intracellular membrane compartments, mainly the Golgi apparatus and the endoplasmic reticulum where palmitoylation likely occurs. 14,15 Since their discovery in 2002, increasing numbers of DHHC-substrate pairs have been identified allowing a deeper comprehension of palmitoylation regulation. 16 Fas palmitoylation occurs on an intracellular cysteine adjacent to the transmembrane domain (cysteine 199 in human) and is critical for its ability to trigger cell death. 8,9 At the molecular level, we and others already reported that the pro-death role of Fas palmitoylation relies on (i) the formation of supramolecular Fas aggregates 9 and (ii) Fas targeting in nanodomains enriched in cholesterol and glycosphingolipids, which is a prerequisite for proper activation of Fas-induced cell death. 8,[17][18][19][20][21] In these domains and upon FasL...

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“…6 Although not all cell types show the raft-dependency of CD95/Fas clustering, 7,8 in lymphocytic cells, the GEM-dependency of the initiation of receptor clustering and signaling was demonstrated by using cholesterol depleting agents, such as methyl-b-cyclodextrin (MbCD). 9 In addition, it was hypothesized 10,11 that a portion of intracellular GD3 can play a role in apoptotic machinery. Activation of death receptors (CD95/Fas, TNFa receptor) induces an intracellular flow of GD3, probably carried entirely by raft-containing vesicular transport.…”

Section: Introductionmentioning

confidence: 99%

Lipid microdomains contribute to apoptosis-associated modifications of mitochondria in T cells

Giammarioli²,

et al. 2005

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Plasma membrane lipid microdomains have been considered as a sort of 'closed chamber', where several subcellular activities, including CD95/Fas-mediated proapoptotic signaling, take place. In this work we detected GD3 and GM3 gangliosides in isolated mitochondria from lymphoblastoid CEM cells. Moreover, we demonstrated the presence of microdomains in mitochondria by immunogold transmission electron microscopy. We also showed that GD3, the voltagedependent anion channel-1 (VDAC-1) and the fission protein hFis1 are structural components of a multimolecular signaling complex, in which Bcl-2 family proteins (t-Bid and Bax) are recruited. The disruption of lipid microdomains in isolated mitochondria by methyl-b-cyclodextrin prevented mitochondria depolarization induced by GD3 or t-Bid. Thus, mitochondrion appears as a subcompartmentalized organelle, in which microdomains may act as controllers of their apoptogenic programs, including fission-associated morphogenetic changes, megapore formation and function. These results disclose a new scenario in which mitochondria-associated lipid microdomains can act as regulators and catalysts of cell fate.

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An essential role for membrane rafts in the initiation of Fas/CD95‐triggered cell death in mouse thymocytes

Cited by 209 publications

References 28 publications

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

Fas palmitoylation by the palmitoyl acyltransferase DHHC7 regulates Fas stability

Lipid microdomains contribute to apoptosis-associated modifications of mitochondria in T cells

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