A Complex Choice Between Life or Death

Signaling through the tumor necrosis factor (TNF) receptor 1 (TNFR1) can lead to apoptosis or cell survival. Survival depends on recruitment of the TNF receptor 1-associated death domain protein (TRADD) and receptor-interacting protein 1 (RIP1) to the TNFR1 and assembly of a signaling complex that leads to activation of nuclear factor κB (NF-κB). NF-κB stimulates the production of antiapoptotic proteins such as FLIP L (a caspase-8 inhibitor). TNFR1-mediated apoptosis has been widely assumed to involve recruitment of the adaptor Fas-associated death domain protein (FADD) and caspase-8 to the TNFR1 (see Barnhart and Peter). Micheau and Tschopp compared the response to TNF in HT1080 cells (wild-type cells) to that in a variant line that expressed a nondegradable NF-κB inhibitor [IκB (inhibitor of NκB) mutant cells]. Wild-type cells remained viable after treatment with TNF, whereas IκB mutant cells underwent apoptosis. Western analysis of cell lysates and immunoprecipitates indicated that two high-molecular-weight complexes formed after exposure to TNF: an early complex containing TNF, TNFR1, RIP1, TRADD, and TNF receptor-associated factor (TRAF2)--but not FADD or caspase-8--and a late complex containing RIP1, TRADD, TRAF2, FADD, and caspase-8, but not TNF or TNFR1. FLIP L participated in the secondary complex in the apoptosis-resistant line. The first complex was associated with the cell membrane; the second was found in the cytosol. Experiments using a FADD dominant-negative mutant indicated that RIP1 association with caspase-8 depended on FADD. Thus, TNFR1-dependent apoptosis appears to involve the sequential formation of two signaling complexes; if NF-κB pathways are activated sufficiently, FLIP L associates with the second complex and thereby inhibits apoptosis. O. Micheau, J. Tschopp, Induction of TNF receptor 1-mediated apoptosis via two sequential signaling complexes. Cell 114 , 181-190 (2003). [Online Journal] B. C. Barnhart, M. E. Peter, The TNF receptor 1: A split personality complex. Cell 114 , 148-150 (2003). [Online Journal]