Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1α-mediated NF-κB activation and down-regulation of TRAF2 expression
Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1α-mediated NF-κB activation and down-regulation of TRAF2 expression
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DOI：
10.1128/mcb.26.8.3071-3084.2006
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发表时间：
2006-04-01
影响因子：
5.3
通讯作者：
Exton, JH
中科院分区：
文献类型：
--
作者：
Hu, P;Han, Z;Exton, JH
核因子-kappaB通过调节线粒体和死亡受体的凋亡通路，对确定细胞对凋亡刺激的敏感性至关重要。内质网(ER)是一种新的细胞凋亡信号起始物。然而，内质网应激激活核因子-kappaB的机制及其在调控内质网应激诱导的细胞死亡中的作用还很不清楚。在这里，我们报告了，作为对内质网应激的响应，IKK通过适配蛋白TRAF2与IRE1α形成复合体。内质网应激诱导的NF-kappa B活性在IRE1α基因敲除细胞和IRE1α(-/-)MEF中受损。然而，我们发现，抑制核因子-kappa B以caspase-8依赖的方式显著减少内质网应激诱导的细胞死亡。基因表达分析表明，内质网应激诱导的肿瘤坏死因子α表达依赖于IRE1α和核因子-kappaB。阻断肿瘤坏死因子受体1信号通路可显著抑制内质网应激诱导的细胞死亡。进一步的研究表明，内质网应激诱导TRAF2表达下调，从而削弱了肿瘤坏死因子-α诱导的核因子-kappaB和c-jun氨基末端激酶的激活，使肿瘤坏死因子-α从一个弱的细胞凋亡诱导剂转变为一个强大的细胞凋亡诱导剂。因此，内质网应激诱导了两种信号，即肿瘤坏死因子-α诱导和TRAF2下调。它们协同工作，通过膜死亡受体放大内质网启动的凋亡信号。
NF-kappa B is critical for determining cellular sensitivity to apoptotic stimuli by regulating both mitochondrial and death receptor apoptotic pathways. The endoplasmic reticulum (ER) emerges as a new apoptotic signaling initiator. However, the mechanism by which ER stress activates NF-kappa B and its role in regulation of ER stress-induced cell death are largely unclear. Here, we report that, in response to ER stress, IKK forms a complex with IRE1 alpha through the adapter protein TRAF2. ER stress-induced NF-kappa B activation is impaired in IRE1 alpha knockdown cells and IRE1 alpha(-/-) MEFs. We found, however, that inhibiting NF-kappa B significantly decreased ER stress-induced cell death in a caspase-8-dependent manner. Gene expression analysis revealed that ER stress-induced expression of tumor necrosis factor alpha (TNF-alpha) was IRE1 alpha and NF-kappa B dependent. Blocking TNF receptor 1 signaling significantly inhibited ER stress-induced cell death. Further studies suggest that ER stress induces down-regulation of TRAF2 expression, which impairs TNF-alpha-induced activation of NF-kappa B and c-Jun N-terminal kinase and turns TNF-alpha from a weak to a powerful apoptosis inducer. Thus, ER stress induces two signals, namely TNF-alpha induction and TRAF2 down-regulation. They work in concert to amplify ER-initiated apoptotic signaling through the membrane death receptor.