Regulated commitment of TNF receptor signaling:: A molecular switch for death or activation

Tumor necrosis factor receptor (TNFR) superfamily members can induce a context-dependent apoptosis or cell activation. However, the mechanisms by which these opposing programs are selected remain unclear. We show that in T cells, TNFR2 (TNFRSF1B) signaling is dramatically affected by the intracellular mediator RIP, a protein Ser/Thr kinase required for NF-kappa B activation by TNFR1 (TNFRSF1A). In the presence of RIP, TNFRP triggers cell death, whereas in the absence of RIP, TNFR2 activates NF-kappa B. RIP is induced during IL2-driven T cell proliferation, and its inhibition reduces susceptibility to TNF-dependent apoptosis. Evidence that signaling outputs are shaped by intracellular constraints helps reconcile conflicting views of TNFR1 and TNFRP as apoptotic mediators.