NEMO/IKKgamma regulates an early NF-kappaB-independent cell-death checkpoint during TNF signaling.
NEMO/IKKgamma regulates an early NF-kappaB-independent cell-death checkpoint during TNF signaling.
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DOI：
10.1038/cdd.2009.41
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发表时间：
2009-09
影响因子：
12.4
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TNF受体1（TNFR 1）连接可导致细胞存活或细胞死亡。是什么决定了两种相反的反应中的哪一种被触发还不完全清楚。目前的模型表明，是NF-κB通路的激活及其对促存活基因的诱导，或其缺乏，决定了结果。NF-κB必需修饰物（NEMO）/IκB激酶γ（IKKγ）缺陷细胞对细胞凋亡高度敏感，由于NEMO对于NF-κB活化至关重要，因此认为这是由于缺乏NF-κB所致。这项研究表明，这一假设是不正确的，NEMO有另一个抗凋亡的功能，是独立的NF-κB通路中的作用。NEMO阻止受体相互作用蛋白-1（RIP 1）在NF-κ B介导的抗凋亡基因诱导之前与半胱天冬酶-8结合。在没有NEMO的情况下，RIP 1与半胱天冬酶-8结合，导致快速肿瘤坏死因子（TNF）诱导的细胞凋亡。这些结果表明TNF刺激后存在两个细胞死亡检查点：一个是早期的转录非依赖性检查点，NEMO通过该检查点抑制RIP 1激活caspase级联反应，随后是一个依赖于NF-κ B介导的促存活基因转录的晚期检查点。
TNF receptor 1 (TNFR1) ligation can result in cell survival or cell death. What determines which of the two opposing responses is triggered is not fully understood. The current model suggests that it is the activation of the NF-κB pathway and its induction of pro-survival genes, or the lack thereof, which determines the outcome. NF-κB essential modifier (NEMO)/IκB kinase gamma (IKKγ)-deficient cells are highly sensitive to apoptosis and since NEMO is essential for NF-κB activation, it has been assumed that this is due to the lack of NF-κB. This study demonstrates that this assumption was incorrect and that NEMO has another anti-apoptotic function that is independent of its role in the NF-κB pathway. NEMO prevents receptor interacting protein-1 (RIP1) from engaging CASPASE-8 prior to NF-κB-mediated induction of anti-apoptotic genes. Without NEMO, RIP1 associates with CASPASE-8 resulting in rapid tumor necrosis factor (TNF)-induced apoptosis. These results suggest that there are two cell death checkpoints following TNF stimulation: an early transcription-independent checkpoint whereby NEMO restrains RIP1 from activating the caspase cascade, followed by a later checkpoint dependent on NF-κB-mediated transcription of pro-survival genes.