Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes
Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes
复制标题
DOI：
10.1016/s0092-8674(03)00521-x
复制
发表时间：
2003-07-25
期刊：
影响因子：
64.5
通讯作者：
Tschopp, J
中科院分区：
文献类型：
--
作者：
Micheau, O;Tschopp, J
肿瘤坏死因子受体I(TNFR1)诱导的细胞凋亡被认为是通过FADD和caspase-8向受体复合体募集而进行的。TNFR1信号也被认为可以激活转录因子NF-kappaB，促进生存。细胞死亡和存活之间的这一决定的仲裁机制尚不清楚。我们报道了TNFR1诱导的细胞凋亡涉及两个顺序的信号复合体。最初的质膜结合复合体(Complex I)由TNFR1、接头Tradd、激酶RIP1和TRAF2组成，能迅速激活核因子-kappaB。在第二步中，Tradd和RIP1与FADD和caspase-8结合，形成细胞质复合体(复合体II)。当核因子-kappaB被复合体I激活时，复合体II含有caspase-8抑制剂FLIPL，细胞存活。因此，TNFR1介导的信号转导包括一个检查点，在初始信号(通过复合体I，NF-kappaB)未能被激活的情况下，导致细胞死亡(通过复合体II)。
Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappaB and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappaB. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappaB is activated by complex I, complex II harbors the caspase-8 inhibitor FLIPL and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappaB) fails to be activated.