TNFRSF

TNFRSF, the tumor necrosis factor receptor superfamily, is a diverse group of type I transmembrane receptors that bind ligands of the TNF ligand superfamily. Members share extracellular cysteine-rich domains and transmit signals through their cytoplasmic tails, with some containing death domains that enable apoptotic signaling while others promote survival and activation.

Ligands for TNFRSF receptors include TNF-α, lymphotoxin-α (TNF-β), CD40L, Fas ligand (FasL), and TRAILs, as well as RANKL. Receptor engagement typically induces receptor trimerization and recruitment of adaptor proteins such as TRADD, FADD, and members of the TRAF family, which then steer downstream signaling toward pathways that regulate inflammation, immunity, and cell fate.

Signaling outcomes vary by receptor but commonly involve activation of NF-κB and MAP kinase pathways, promoting cell survival, proliferation, and inflammatory responses. Some TNFRSF members can initiate caspase-dependent apoptosis when associated with death-domain signaling complexes, illustrating the family’s dual capacity to support immune activation or programmed cell death.

Physiologically, TNFRSF signaling governs immune system development and function, including T and B cell activation, dendritic cell survival, and co-stimulation, as well as osteoclast differentiation and lymphoid organogenesis. Dysregulation of TNFRSF signaling is implicated in inflammatory and autoimmune diseases, infections, and cancer, making components of the family targets for therapeutic intervention.

Prominent TNFRSF receptors include TNFR1 (TNFRSF1A) and TNFR2 (TNFRSF1B) for TNF; CD40 (TNFRSF5); CD27 (TNFRSF7); 4-1BB (TNFRSF9); OX40 (TNFRSF4); GITR (TNFRSF18); HVEM (TNFRSF14); and the TRAIL receptors DR4/DR5 (TNFRSF10A/B). RANK (TNFRSF11A) and its ligand RANKL (TNFSF11) regulate bone metabolism and immunity.