The fuzzy logic of the death-inducing signaling complex in lymphocytes

Receptors belonging to the tumor necrosis factor receptor family have long been thought to play an important role in the regulation of immunity. Although this family is composed of a large number of surface receptors that potentiate myriad functions in vivo, a subset is known to directly convey apoptotic signals. One such molecule belonging to this subset is CD95. Ligation of CD95 instigates the formation of a complex known as the death-inducing signaling complex or DISC, which is composed of molecules including FADD (Fas associated with death domain) and RIP (receptor-interacting kinase), as well as procaspases-8 and -10, and a caspase-8-like molecule that lacks proteolytic activity called c-FLIP. Although the DISC was initially thought to serve an exclusively proapoptotic role, humans and mice with defects in various components of this complex demonstrate a variety of developmental and hematopoietic defects that are not apparently due to aberrant apoptosis. These findings paint a far more complex picture of the numerous components of the DISC, and provide evidence that these complexes serve nonapoptotic functions. Herein, we summarize the experimental evidence challenging the notion that the DISC imparts an exclusively apoptotic function and provide hypotheses to account for these alternative roles. Rather than operating as a binary system, we propose that the DISCs formed around various DRs transduce signals leading to a variety of cellular fates.