A JNK-dependent pathway is required for TNFalpha-induced apoptosis.
A JNK-dependent pathway is required for TNFalpha-induced apoptosis.
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发表时间：
2003
期刊：
影响因子：
64.5
通讯作者：
Yibin Deng;Xiaoyang Ren;Lin Yang;Yahong Lin;Xiangwei Wu
中科院分区：
文献类型：
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作者：
Yibin Deng;Xiaoyang Ren;Lin Yang;Yahong Lin;Xiangwei Wu
肿瘤坏死因子受体信号通路可同时激活转录因子caspase8、核因子-kappaB和蛋白激酶JNK。虽然caspase 8的激活是肿瘤坏死因子α诱导的细胞凋亡所必需的，而核因子-kappaB的诱导抑制了细胞死亡，但JNK激活在肿瘤坏死因子α信号转导中的确切作用尚不清楚。在这里，我们报告了TNFpha介导的caspase8的切割和凋亡需要一个涉及JNK、BID和Smac/Diablo的顺序通路。JNK的激活诱导不依赖于caspase 8的BID在不同的位点切割，产生BID切割产物jBid。JBid易位到线粒体导致Smac/Diablo优先释放，而不是细胞色素c。释放的Smac/DIABLO随后破坏TRAF2-cIAP1复合体。我们认为，JNK途径是必需的，以解除TRAF2-cIAP1对caspase 8激活和诱导细胞凋亡的抑制。此外，我们的发现定义了内在和外在细胞死亡途径之间的串扰机制。
Tumor necrosis factor (TNFalpha) receptor signaling can simultaneously activate caspase 8, the transcription factor, NF-kappaB and the kinase, JNK. While activation of caspase 8 is required for TNFalpha-induced apoptosis, and induction of NF-kappaB inhibits cell death, the precise function of JNK activation in TNFalpha signaling is not clearly understood. Here, we report that TNFalpha-mediated caspase 8 cleavage and apoptosis require a sequential pathway involving JNK, Bid, and Smac/DIABLO. Activation of JNK induces caspase 8-independent cleavage of Bid at a distinct site to generate the Bid cleavage product jBid. Translocation of jBid to mitochondria leads to preferential release of Smac/DIABLO, but not cytochrome c. The released Smac/DIABLO then disrupts the TRAF2-cIAP1 complex. We propose that the JNK pathway described here is required to relieve the inhibition imposed by TRAF2-cIAP1 on caspase 8 activation and induction of apoptosis. Further, our findings define a mechanism for crosstalk between intrinsic and extrinsic cell death pathways.