Principles and mechanisms of CD95 activation

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 pathways is not a simple consequence of ligand binding but is the fine-tuned result of a complex interplay of various molecular mechanisms that eventually determine the strength and quality of the CD95 response. There is growing evidence that different forms of CD95 stimulation trigger the assembly of CD95 signaling complexes of distinct composition. Moreover, the formation of signaling competent CD95 complexes is a multistep process and the subject of regulation by various cellular cues. This review addresses the relevance of the molecular nature of the CD95-stimulating agonist for the quality of the CD95 response and discusses the importance of modification, clustering, internalization, and lipid raft and actin association of CD95 for CD95 activity.

Sphingolipid Organization in the Plasma Membrane and the Mechanisms That Influence It

“…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.…”

“…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).…”

Lipid raft-mediated Fas/CD95 apoptotic signaling in leukemic cells and normal leukocytes and therapeutic implications

“…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].…”

Fas Receptor: An Overview

“…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.…”