TNFRSF10A

TNFRSF10A encodes death receptor 4 (DR4), also known as TRAIL receptor 1 (TRAIL-R1). It is a member of the tumor necrosis factor receptor (TNFR) superfamily and functions as a transmembrane receptor for the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). The extracellular domain contains cysteine-rich repeats that bind TRAIL, while the cytoplasmic death domain mediates apoptotic signaling.

Upon TRAIL binding, DR4 recruits the adaptor protein FADD and procaspase-8 to form the death-inducing signaling complex (DISC), leading to activation of caspase-8 and initiation of the caspase cascade that drives apoptosis. In some cellular contexts, caspase-8 activation can also engage mitochondrial pathways via Bid cleavage, amplifying the apoptotic response.

DR4 is expressed in a variety of normal tissues and in many tumor cells. TRAIL signaling through DR4 contributes to immune surveillance by cytotoxic T cells and natural killer cells, which can induce apoptosis in stressed or malignant cells. Signaling is regulated by cellular context and can be inhibited by factors such as c-FLIP and by decoy receptors TRAIL-R3 (TNFRSF10C) and TRAIL-R4 (TNFRSF10D), which can bind TRAIL without transmitting an apoptotic signal.

Because of its potential to selectively induce apoptosis in cancer cells, DR4 has been explored as a therapeutic target. Approaches include recombinant TRAIL and agonistic antibodies directed at DR4, though clinical efficacy has varied and is influenced by receptor expression, signaling regulators, and resistance mechanisms.