Hsp70 promotes TNF-mediated apoptosis by binding IKKγ and impairing NF-κB survival signaling
Hsp70 promotes TNF-mediated apoptosis by binding IKKγ and impairing NF-κB survival signaling
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DOI：
10.1101/gad.1188204
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发表时间：
2004-06-15
影响因子：
10.5
通讯作者：
Rigby, AC
中科院分区：
文献类型：
--
作者：
Ran, RQ;Lu, AG;Rigby, AC
主要的热休克蛋白Hsp 70可以通过直接干扰线粒体凋亡途径来防止细胞死亡。然而，Hsp 70也使细胞对某些凋亡刺激物如TNF敏感。关于Hsp 70如何促进细胞凋亡知之甚少。我们在这里证明，热休克蛋白70通过特异性结合IkappaB激酶γ（IKK γ）的卷曲螺旋结构域来抑制IKK活性，从而抑制NF-κ B依赖性抗凋亡基因诱导，从而促进TNF杀伤。与Hsp 70相互作用的IKK γ突变体竞争性抑制Hsp 70-IKK γ相互作用并缓解热介导的NF-κ B抑制。RNA干扰消除Hsp 70表达可挽救TNF介导的细胞死亡虽然TNF本身可能足以或可能不足以触发细胞凋亡，但当Hsp 70表达增加到高水平以破坏NF-κ B信号传导时，TNF触发的细胞凋亡被启动或变得更糟。这些结果为Hsp 70在死亡受体介导的细胞死亡中的促凋亡行为的分子机制提供了重要的新见解。
The major heat shock protein, Hsp70, can protect against cell death by directly interfering with mitochondrial apoptosis pathways. However, Hsp70 also sensitizes cells to certain apoptotic stimuli like TNF. Little is known about how Hsp70 enhances apoptosis. We demonstrate here that Hsp70 promotes TNF killing by specifically binding the coiled-coil domain of IkappaB kinase gamma (IKKgamma) to inhibit IKK activity and consequently inhibit NF-kappaB-dependent antiapoptotic gene induction. An IKKgamma mutant, which interacts with Hsp70, competitively inhibits the Hsp70-IKKgamma interaction and relieves heat-mediated NF-kappaB suppression. Depletion of Hsp70 expression with RNA interference rescues TNF-mediated cell death. Although TNF may or may not be sufficient to trigger apoptosis on its own, TNF-triggered apoptosis was initiated or made worse when Hsp70 expression increased to high levels to disrupt NF-kappaB signaling. These results provide significant novel insights into the molecular mechanism for the pro-apoptotic behavior of Hsp70 in death-receptor-mediated cell death.