Abstract:CD95 (Apo1/Fas) has been originally identified as the target of cell death-inducing antibodies. The recognition of CD95 as an apoptosis-triggering receptor represents one of the early milestones in the apoptosis field. Moreover, the research on CD95-induced cell death fostered various other discoveries of broad and general relevance in cell biology, for example, the identification of caspase 8 as the initiator caspase of the extrinsic apoptosis pathway. Activation of CD95-associated intracellular signaling pat… Show more
“…Studies of the trafficking of GD3, a disialoganglioside ganglioside, during CD95/Fas-mediated apoptosis seem to support this possibility. CD95/Fas-mediated apoptosis is initiated by the binding of either the Fas ligand or an antagonistic Fas antibody to CD95, a member of the TNF-receptor superfamily that is also called Fas (Wajant, 2014). This binding induces the recruitment of Fas-associated death domain (FADD) to the CD95 death domain.…”
Section: Glycosphingolipid Redistribution Induced By Antigen Crosslinmentioning
confidence: 99%
“…This binding induces the recruitment of Fas-associated death domain (FADD) to the CD95 death domain. Next, procaspase-8 is recruited to FADD's death effector domain, forming the death-inducing signaling complex (DISC) that elicits apoptosis (Algeciras-Schimnich et al, 2002; Wajant, 2014). Interest in GD3 involvement in CD95/Fas-mediated apoptosis began with the discovery that the crosslinking of CD95 on lymphoid and myeloid cells induces GD3 production, and this ganglioside is required for apoptosis (De Maria et al, 1997).…”
Section: Glycosphingolipid Redistribution Induced By Antigen Crosslinmentioning
Sphingolipids are structural components in the plasma membranes of eukaryotic cells. Their metabolism produces bioactive signaling molecules that modulate fundamental cellular processes. The segregation of sphingolipids into distinct membrane domains is likely essential for cellular function. This review presents the early studies of sphingolipid distribution in the plasma membranes of mammalian cells that shaped the most popular current model of plasma membrane organization. The results of traditional imaging studies of sphingolipid distribution in stimulated and resting cells are described. These data are compared with recent results obtained with advanced imaging techniques, including super-resolution fluorescence detection and high-resolution secondary ion mass spectrometry (SIMS). Emphasis is placed on the new insight into the sphingolipid organization within the plasma membrane that has resulted from the direct imaging of stable isotope-labeled lipids in actual cell membranes with high-resolution SIMS. Super-resolution fluorescence techniques have recently revealed the biophysical behaviors of sphingolipids and the unhindered diffusion of cholesterol analogs in the membranes of living cells are ultimately in contrast to the prevailing hypothetical model of plasma membrane organization. High-resolution SIMS studies also conflicted with the prevailing hypothesis, showing sphingolipids are concentrated in micrometer-scale membrane domains, but cholesterol is evenly distributed within the plasma membrane. Reductions in cellular cholesterol decreased the number of sphingolipid domains in the plasma membrane, whereas disruption of the cytoskeleton eliminated them. In addition, hemagglutinin, a transmembrane protein that is thought to be a putative raft marker, did not cluster within sphingolipid-enriched regions in the plasma membrane. Thus, sphingolipid distribution in the plasma membrane is dependent on the cytoskeleton, but not on favorable interactions with cholesterol or hemagglutinin. The alternate views of plasma membrane organization suggested by these findings are discussed.
“…Studies of the trafficking of GD3, a disialoganglioside ganglioside, during CD95/Fas-mediated apoptosis seem to support this possibility. CD95/Fas-mediated apoptosis is initiated by the binding of either the Fas ligand or an antagonistic Fas antibody to CD95, a member of the TNF-receptor superfamily that is also called Fas (Wajant, 2014). This binding induces the recruitment of Fas-associated death domain (FADD) to the CD95 death domain.…”
Section: Glycosphingolipid Redistribution Induced By Antigen Crosslinmentioning
confidence: 99%
“…This binding induces the recruitment of Fas-associated death domain (FADD) to the CD95 death domain. Next, procaspase-8 is recruited to FADD's death effector domain, forming the death-inducing signaling complex (DISC) that elicits apoptosis (Algeciras-Schimnich et al, 2002; Wajant, 2014). Interest in GD3 involvement in CD95/Fas-mediated apoptosis began with the discovery that the crosslinking of CD95 on lymphoid and myeloid cells induces GD3 production, and this ganglioside is required for apoptosis (De Maria et al, 1997).…”
Section: Glycosphingolipid Redistribution Induced By Antigen Crosslinmentioning
Sphingolipids are structural components in the plasma membranes of eukaryotic cells. Their metabolism produces bioactive signaling molecules that modulate fundamental cellular processes. The segregation of sphingolipids into distinct membrane domains is likely essential for cellular function. This review presents the early studies of sphingolipid distribution in the plasma membranes of mammalian cells that shaped the most popular current model of plasma membrane organization. The results of traditional imaging studies of sphingolipid distribution in stimulated and resting cells are described. These data are compared with recent results obtained with advanced imaging techniques, including super-resolution fluorescence detection and high-resolution secondary ion mass spectrometry (SIMS). Emphasis is placed on the new insight into the sphingolipid organization within the plasma membrane that has resulted from the direct imaging of stable isotope-labeled lipids in actual cell membranes with high-resolution SIMS. Super-resolution fluorescence techniques have recently revealed the biophysical behaviors of sphingolipids and the unhindered diffusion of cholesterol analogs in the membranes of living cells are ultimately in contrast to the prevailing hypothetical model of plasma membrane organization. High-resolution SIMS studies also conflicted with the prevailing hypothesis, showing sphingolipids are concentrated in micrometer-scale membrane domains, but cholesterol is evenly distributed within the plasma membrane. Reductions in cellular cholesterol decreased the number of sphingolipid domains in the plasma membrane, whereas disruption of the cytoskeleton eliminated them. In addition, hemagglutinin, a transmembrane protein that is thought to be a putative raft marker, did not cluster within sphingolipid-enriched regions in the plasma membrane. Thus, sphingolipid distribution in the plasma membrane is dependent on the cytoskeleton, but not on favorable interactions with cholesterol or hemagglutinin. The alternate views of plasma membrane organization suggested by these findings are discussed.
“…When it comes to DRs, Fas/CD95 (also called APO-1) is considered to be the prototypic and major member of the death-receptor family, a subgroup of the TNFRSF, which also includes the TRAIL receptors TRAIL-R1 (a.k.a., DR4) and TRAIL-R2 (a.k.a., DR5) and can transmit apoptotic signals through the presence of a cytoplasmic DD [46,47]. The interaction of Fas/CD95 with its cognate ligand (FasL/CD95L) results in the following: 1) receptor oligomerization and aggregation; 2) recruitment of the adaptor protein FADD, through homotypic interaction between the DDs of both Fas/CD95 and FADD; and 3) subsequent binding of procaspase-8 or -10 to FADD through their respective DEDs that eventually leads to caspase-8/10 activation [48].…”
Plasma membrane is now recognized to contain tightly packed cholesterol/sphingolipid-rich domains, known as lipid or membrane rafts, which are more ordered than the surrounding lipid bilayer. Lipid rafts are crucial for the compartmentalization of signaling processes in the membrane, mostly involved in cell survival and immune response. However, in the last 15 years, a large body of evidence has also identified raft platforms as scaffolds for the recruitment and clustering of death receptor Fas/CD95 and downstream signaling molecules, leading to the concept of death-promoting lipid rafts. This raft-Fas/CD95 coclustering was first described at the early 2000s as the underlying mechanism for the proapoptotic action of the alkylphospholipid analog edelfosine in leukemic cells, hence facilitating protein-protein interactions and conveying apoptotic signals independently of Fas/CD95 ligand. Edelfosine induces apoptosis in hematologic cancer cells and activated T-lymphocytes. Fas/CD95 raft coclustering is also promoted by Fas/CD95 ligand, agonistic Fas/CD95 antibodies, and additional antitumor drugs. Thus, death receptor recruitment in rafts is a physiologic process leading to cell demise that can be pharmacologically modulated. This redistribution and local accumulation of apoptotic molecules in membrane rafts, which are usually accompanied by displacement of survival signaling molecules, highlight how alterations in the apoptosis/survival signaling balance in specialized membrane regions modulate cell fate. Membrane rafts might also modulate apoptotic and nonapoptotic death receptor signaling. Here, we discuss the role of lipid rafts in Fas/CD95-mediated apoptotic cell signaling in hematologic cancer cells and normal leukocytes, with a special emphasis on their involvement as putative therapeutic targets in cancer and autoimmune diseases.
“…It belongs to the death receptor family, a subgroup of the Tumor Necrosis Factor (TNF)/ Nerve Growth Factor (NGF) receptor superfamily, 1,2 and acts as the target of cell death-inducing antibodies. 3 These cell surface cytokine receptors are able to initiate an apoptotic signaling cascade after binding a group of structurally related ligands or specific antibodies. In addition to its apoptotic function, it has other cellular responses including migration, invasion, inflammation, and proliferation.…”
The FAS receptor (FasR), also known as apoptosis antigen 1 (APO-1 or APT), cluster of differentiation 95 (CD95) or tumor necrosis factor receptor superfamily 6 (TNFRSF6) is a protein that in humans is encoded by the FAS gene. Engagement of the cell death surface receptor Fas by Fas ligand (FasL) results in apoptotic cell death, mediated by caspase activation. Cell death mediated via Fas/FasL interaction is important for homeostasis of different cell types. In this review, we want to highlight the role of Fas receptor in different dermatologic disorders. This would definitely help our understanding of its important role in dermatology that can open a new era in using anti-Fas biologic therapy in the future management of such disorders.
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