deathligand

Death ligands are signaling molecules that induce programmed cell death by engaging specific death receptors on target cells. They are primarily members of the tumor necrosis factor (TNF) superfamily and related families. Binding of a death ligand to its receptor often triggers an extrinsic apoptotic pathway, shaping immune responses, tissue turnover, and development. In some contexts, death signaling can also provoke inflammatory or necroptotic outcomes rather than apoptosis.

Prominent examples include Fas ligand (FasL/CD95L), TNF, and TRAIL (TNF-related apoptosis-inducing ligand). Their receptors include Fas (CD95), TNF receptor 1 (TNFR1), and TRAIL receptors DR4 (TRAILR1) and DR5 (TRAILR2). Decoy receptors and soluble receptor forms can modulate signaling strength and outcome, preventing unintended cell loss.

Mechanistically, ligand binding promotes receptor trimerization and formation of a death-inducing signaling complex (DISC) that recruits adaptor proteins such as FADD and initiator caspases (notably caspase-8). Activated caspases then propagate the cascade leading to cell demolition by executioner caspases (e.g., caspase-3, -7). In some cells, caspase-8 activity inhibits necroptosis; when caspase-8 is inhibited, death signals can engage RIPK1, RIPK3, and MLKL to induce necroptosis. TNF signaling can also activate NF-κB and promote survival or inflammation, depending on cellular context.

Physiological roles include removal of infected or damaged cells, regulation of immune cell homeostasis, and developmental processes. Dysregulation of death-ligand pathways is linked to cancer, autoimmunity, and neurodegenerative diseases. Therapeutically, components of these pathways are targets for cancer treatments, including agonistic antibodies and ligand-based therapies, though clinical use requires careful management of selectivity and toxicity.