FADD regulates NF-κB activation and promotes ubiquitination of cFLIPL to induce apoptosis.
FADD regulates NF-κB activation and promotes ubiquitination of cFLIPL to induce apoptosis.
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DOI：
10.1038/srep22787
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发表时间：
2016-03-14
影响因子：
4.6
通讯作者：
Pathak C
中科院分区：
文献类型：
--
作者：
Ranjan K;Pathak C
肿瘤坏死因子-α可诱导NF-κB及其相关基因产物细胞flic样抑制蛋白（cfllipl）的活化，促进细胞存活。在此之前，我们证明了在HEK 293T细胞中，Fas相关死亡结构域（FADD）的异位表达会降低cfllipl的表达，并转导caspase -8介导的凋亡，而不依赖于FasL的刺激。然而，FADD介导的cFLIP和NF-κB信号消融决定细胞死亡或存活的潜在分子机制尚不清楚。在这里，我们探索了FADD介导的凋亡细胞死亡的一种新的分子机制，该机制由cFLIPL的泛素化和NF-κB活化的抑制所指导，不依赖于TNF-α的刺激。我们发现FADD的诱导表达与procaspase-8紧密相互作用，并阻止cFLIPL从死亡诱导信号复合物（DISC）中释放出来。此外，FADD负调控细胞凋亡抑制蛋白2 （cIAP2）和Bcl-2。此外，FADD抑制cIAP2的表达，并与RIP1和procaspase-8相互作用，完成凋亡细胞死亡信号传导。有趣的是，FADD还被发现促进JNK1介导的E3泛素连接酶ITCH的激活，从而降解可能导致细胞凋亡开始的cFLIPL。因此，FADD是决定细胞死亡或存活命运的重要调节因子。
Tumor Necrosis Factor-α canonically induces the activation of NF-κB and associated gene product cellular FLICE-like inhibitory protein (cFLIPL) to promote cell survival. Previously, we demonstrated that ectopic expression of the Fas associated death domain (FADD) diminishes the expression of cFLIPL and transduces caspases-8 mediated apoptosis, independent of FasL stimulation in HEK 293T cells. However, the underlying molecular mechanism of FADD mediated ablation of cFLIP and NF-κB signaling to determining the fate of cell death or survival remains elusive. Here, we explored a novel molecular mechanism of FADD mediated apoptotic cell death that was directed by ubiquitination of cFLIPL and inhibition of NF-κB activation, independent of TNF-α stimulation. We found that induced expression of FADD firmly interacts with procaspase-8 and precludes cFLIPL to from the death inducing signaling complex (DISC). In addition, FADD negatively regulates cellular inhibitor of apoptosis protein 2 (cIAP2) and Bcl-2. Furthermore, FADD restrains cIAP2 expression and interacts with RIP1 and procaspase-8 to accomplish apoptotic cell death signaling. Interestingly, FADD was also found to promote JNK1 mediated activation of E3 ubiquitin ligase ITCH to degrade cFLIPL that may lead to commencement of apoptosis. Thus, FADD is an important regulator for determining the fate of cell death or survival.