Cleavage of the death domain kinase RIP by Caspase-8 prompts TNF-induced apoptosis
Cleavage of the death domain kinase RIP by Caspase-8 prompts TNF-induced apoptosis
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DOI：
10.1101/gad.13.19.2514
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发表时间：
1999-10-01
影响因子：
10.5
通讯作者：
Liu, ZG
中科院分区：
文献类型：
--
作者：
Lin, Y;Devin, A;Liu, ZG
虽然TNF信号转导的分子机制已在很大程度上阐明，但调节生命和死亡平衡的原理仍然未知。我们在这里报告的死亡结构域激酶RIP，TNF信号复合物的关键组成部分，被切割的Caspase-8在TNF诱导的细胞凋亡。切割位点定位于RIP的324位的天冬氨酸。我们证明RIP的裂解导致TNF诱导的NF-κ B活化的阻断。裂解产物RIPc可增强TRADD与FADD/MORT 1的相互作用，增加细胞对TNF的敏感性。最重要的是，Caspase-8抗性RIP突变体保护细胞免受TNF诱导的细胞凋亡。这些结果表明，RIP的切割是TNF诱导的细胞凋亡的一个重要过程。此外，RIP切割也检测到其他死亡受体介导的凋亡。因此，我们的研究为死亡受体介导的细胞凋亡提供了一个潜在的机制，使细胞从生转死。
Although the molecular mechanisms of TNF signaling have been largely elucidated, the principle that regulates the balance of life and death is still unknown. We report here that the death domain kinase RIP, a key component of the TNF signaling complex, was cleaved by Caspase-8 in TNF-induced apoptosis. The cleavage site was mapped to the aspartic acid at position 324 of RIP. We demonstrated that the cleavage of RIP resulted in the blockage of TNF-induced NF-kappa B activation. RIPc, one of the cleavage products, enhanced interaction between TRADD and FADD/MORT1 and increased cells' sensitivity to TNF. Most importantly, the Caspase-8 resistant RIP mutants protected cells against TNF-induced apopotosis. These results suggest that cleavage of RIP is an important process in TNF-induced apoptosis. Further more, RIP cleavage was also detected in other death receptor-mediated apoptosis. Therefore, our study provides a potential mechanism to convert cells from life to death in death receptor-mediated apoptosis.