The study investigates the role of the death domain kinase RIP in TNF-induced apoptosis. RIP, a key component of the TNF signaling complex, is cleaved by Caspase-8, leading to the blockage of TNF-induced NF-κB activation. The cleavage site is identified as aspartic acid at position 324. One of the cleavage products, RIPc, enhances the interaction between TRADD and FADD/MORT1, increasing cells' sensitivity to TNF. Caspase-resistant RIP mutants protect cells against TNF-induced apoptosis. RIP cleavage is also observed in other death receptor-mediated apoptosis, suggesting it is a common process. These findings provide a potential mechanism for converting cells from life to death in death receptor-mediated apoptosis.The study investigates the role of the death domain kinase RIP in TNF-induced apoptosis. RIP, a key component of the TNF signaling complex, is cleaved by Caspase-8, leading to the blockage of TNF-induced NF-κB activation. The cleavage site is identified as aspartic acid at position 324. One of the cleavage products, RIPc, enhances the interaction between TRADD and FADD/MORT1, increasing cells' sensitivity to TNF. Caspase-resistant RIP mutants protect cells against TNF-induced apoptosis. RIP cleavage is also observed in other death receptor-mediated apoptosis, suggesting it is a common process. These findings provide a potential mechanism for converting cells from life to death in death receptor-mediated apoptosis.