Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5

Fas (APO-1/CD95) and tumor necrosis factor receptor 1 (TNFR1) trigger apopt osis by recruiting the apoptosis initiator caspase-8 through the adaptor FA DD. Fas binds FADD directly, whereas TNFR1 binds FADD indirectly, through T RADD. TRADD alternatively recruits the NF-kappa B-inducing adaptor RIP. The TNF homolog Apo2L/TRAIL triggers apoptosis through two distinct death rece ptors, DR4 and DR5; however, receptor overexpression studies have yielded c onflicting results on the ligand's signaling mechanism. Apo2L/TRAIL induced homomeric and heteromeric complexes of DR4 and DR5 and stimulated recruitm ent of FADD and caspase-8 and caspase-8 activation in nontransfected cells. TRADD and RIP, which bound TNFR1, did not bind DR4 and DR5. Thus, Apo2L/TR AIL and FasL initiate apoptosis through similar mechanisms, and FADD may be a universal adaptor for death receptors.