Death receptors (Fas and TRAIL receptors) (DRs)

Death receptors are a specialized subset of the tumor necrosis factor receptor (TNFR) superfamily characterized by a conserved intracellular "death domain" (DD) that is essential for transducing apoptotic signals. The primary members engaged by Fas ligand (FasL) and TRAIL (TNF-related apoptosis-inducing ligand) include Fas (CD95/TNFRSF6), TRAIL-R1 (DR4/TNFRSF10A), and TRAIL-R2 (DR5/TNFRSF10B) [UniProt P25445, O00220, O14763]. Upon ligand binding, these receptors undergo oligomerization and recruit the adapter protein FADD and pro-caspase-8 to form the death-inducing signaling complex (DISC), which initiates the extrinsic apoptosis pathway [NIH/StatPearls]. In oncology, these receptors are frequently downregulated or the pathway is inhibited by proteins like c-FLIP, allowing cancer cells to evade programmed cell death [PubMed: 24591636]. Therapeutic development has largely focused on agonistic antibodies and recombinant TRAIL variants to selectively induce apoptosis in malignant cells, though clinical progress has been hampered by challenges such as hepatotoxicity and limited potency [PubMed: 25605115]. Conversely, blocking the Fas/FasL interaction is being investigated as a strategy to prevent excessive cell death in conditions like glioblastoma and autoimmune disorders.

Other names

Fas receptorCD95TNFRSF6TRAIL-R1DR4TNFRSF10ATRAIL-R2DR5TNFRSF10BDeath Receptor 4Death Receptor 5Apo-1Apo-2Killer

Agonism of death receptors to trigger the extrinsic apoptotic pathway via the formation of the death-inducing signaling complex (DISC) and subsequent caspase activation; or inhibition of ligand-receptor interaction to prevent pathological cell death.