The study reveals that the death domain kinase RIP is cleaved by Caspase-8 during TNF-induced apoptosis. Cleavage of RIP at aspartic acid residue 324 blocks its ability to activate NF-κB, which is essential for cell survival. One of the cleavage products, RIPc, enhances the interaction between TRADD and FADD, increasing cell sensitivity to TNF. Caspase-8-resistant RIP mutants protect cells from TNF-induced apoptosis, indicating that RIP cleavage is crucial for the transition from life to death in TNF signaling. Additionally, RIP cleavage was observed in other death receptor-mediated apoptosis, such as Fas and TRAIL pathways. These findings suggest that RIP cleavage is a key regulatory step in death receptor-mediated apoptosis, converting cells from life to death in response to TNF. The study provides a potential mechanism for the regulation of death receptor-mediated apoptosis.The study reveals that the death domain kinase RIP is cleaved by Caspase-8 during TNF-induced apoptosis. Cleavage of RIP at aspartic acid residue 324 blocks its ability to activate NF-κB, which is essential for cell survival. One of the cleavage products, RIPc, enhances the interaction between TRADD and FADD, increasing cell sensitivity to TNF. Caspase-8-resistant RIP mutants protect cells from TNF-induced apoptosis, indicating that RIP cleavage is crucial for the transition from life to death in TNF signaling. Additionally, RIP cleavage was observed in other death receptor-mediated apoptosis, such as Fas and TRAIL pathways. These findings suggest that RIP cleavage is a key regulatory step in death receptor-mediated apoptosis, converting cells from life to death in response to TNF. The study provides a potential mechanism for the regulation of death receptor-mediated apoptosis.