Figure 1. Revising models of TRAIL‐induced formation of cell death and NF‐κB‐inducing signaling complexes.

Left, prevalent model based on spatial hierarchy. TRAIL initially stimulates assembly of a membrane‐localized apoptosis‐inducing signaling complex comprising TRAIL death receptors, FADD, and procaspase‐8 filaments. After release into the cytoplasm, the latter two secondarily form an NF‐κB‐activating complex together with RIP and TRAF2. Notably, models of TNFR1 signaling invoke the opposite order of events. Right, revised model with pathway bifurcation at the receptor level. Proteins required for apoptosis induction and NF‐κB activation are concomitantly recruited to the membrane‐localized TRAIL death receptor signaling complex prior to eventual release in the cytoplasm. Although FADD is an essential part of the revised model, it is no obligate component of the cytosolic complex—while FADD‐deficient cells lack cell death induction or NF‐κB activation after TRAIL stimulation, they are still able to activate NF‐κB and necroptosis in response to TNF. The asterisk indicates fully matured heterotetrameric caspase‐8.