A JNK-dependent pathway is required for TNFα-induced apoptosis
A JNK-dependent pathway is required for TNFα-induced apoptosis
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DOI：
10.1016/s0092-8674(03)00757-8
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发表时间：
2003-10-03
期刊：
影响因子：
64.5
通讯作者：
Wu, XW
中科院分区：
文献类型：
--
作者：
Deng, YB;Ren, XY;Wu, XW
肿瘤坏死因子（TNF α）受体信号传导可以同时激活半胱天冬酶8、转录因子NF-κ B和激酶JNK。虽然半胱天冬酶8的活化是TNF α诱导的细胞凋亡所必需的，并且NF-κ B的诱导抑制细胞死亡，但JNK活化在TNF α信号传导中的精确功能尚不清楚。在这里，我们报告说，TNFa介导的caspase 8裂解和凋亡需要一个连续的途径，涉及JNK，投标，和Smac/DIABLO。JNK的活化诱导Bid在不同位点的半胱天冬酶8非依赖性切割，以产生Bid切割产物jBid。jBid向线粒体的易位导致Smac/DIABLO的优先释放，而不是细胞色素c。然后释放的Smac/DIABLO破坏TRAF 2-cIAP 1复合物。我们建议，JNK通路在这里描述的是需要解除抑制施加的TRAF 2-cIAP 1对caspase 8的激活和诱导细胞凋亡。此外，我们的研究结果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-KB and the kinase, JNK. While activation of caspase 8 is required for TNFalpha-induced apoptosis, and induction of NF-KB inhibits cell death, the precise function of JNK activation in TNFa 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.