Cell death by apoptosis is a tightly regulated physiologi-cal process that enables the elimination of unwanted cells. It is crucial for embryonic development and the maintenance of tissue homeostasis, but also for defense against certain infectious diseases and cancer. Apoptosis can be triggered from outside the cell, generally after cell–cell contact, by a family of transmembrane proteins called death receptors, which belong to the TNF family of receptors. Six human death receptors (Fas [Apo-1, CD95], TNFR-1, TRAMP [WSL-1/Apo-3/DR-3/LARD], TNF-related apoptosis-inducing ligand [TRAIL] R-1 [DR-4], TRAILR-2 [DR-5, TRICK-2, KILLER], and DR-6) have been identified to date (1, 2), and all contain a cytoplasmic sequence named “death domain”(DD) that couples each receptor to caspase cascades essential for the induction of apoptosis. The best studied signaling pathway is the one triggered by binding of Fas ligand (L) to Fas. Schematically, multimerization or clustering of Fas upon binding of the membrane-bound form of FasL recruits the bipartite molecule FADD (Fas-associated death domain, composed of an NH2-terminal death effector domain [DED] and a COOH-terminal DD). FADD binds to Fas (via homophilic DD–DD interactions) and recruits the upstream DED-containing caspase-8 (and probably caspase-10) to the receptor via homophilic DED–DED interactions. Caspase-8 (or-10) within this newly formed death-inducing signaling complex then proteolytically autoactivates itself and initiates apoptosis by subsequent cleavage of downstream effector caspases (caspase-3,-6, and-7)(Fig. 1).

Fas signaling is known to be implicated in peripheral deletion of autoimmune cells, activation-induced T cell death, and CTL-mediated target cell death (for review see references 1 and 3). To avoid inappropriate cell death and disease, however, death receptor signals must be tightly controlled. It is known that death receptor apoptosis can be inhibited at different points: at the receptor level (by receptor endocytosis, soluble ligands, and/or decoy receptors), during signal transduction, and at the effector stage (eg, caspase inhibitors CrmA, p35, and inhibitor of apoptosis proteins [IAPs]). Recently, we identified a new family of viral inhibitors of death receptor–mediated cell death named vFLIPs (FADD-like IL1–converting enzyme [FLICE]/caspase-8–inhibitory proteins) that are found in