The Death Domain Kinase RIP Mediates the TNF-Induced NF-κB Signal

The death domain serine/threonine kinase RIP interacts with the death receptors Fas and tumor necrosis receptor 1 (TNFR1). In vitro, RIP stimulates apoptosis, SAPK/JNK, and NF-κB activation. To define the physiologic role(s) that RIP plays in regulating apoptosis in vivo, we introduced a rip null mutation in mice through homologous recombination. RIP-deficient mice appear normal at birth but fail to thrive, displaying extensive apoptosis in both the lymphoid and adipose tissue and dying at 1–3 days of age. In contrast to a normal thymic anti-Fas response rip −/− cells are highly sensitive to TNFα-induced cell death. Sensitivity to TNFα-mediated cell death in rip −/− cells is accompanied by a failure to activate the transcription factor NF-κB.