The adaptor protein FADD and the initiator caspase-8 mediate activation of NF-κB by TRAIL.
The adaptor protein FADD and the initiator caspase-8 mediate activation of NF-κB by TRAIL.
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DOI：
10.1038/cddis.2012.154
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发表时间：
2012-10-25
影响因子：
9
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中科院分区：
文献类型：
--
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肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand，TRAIL）除了诱导细胞凋亡外，还激活NF-κ B B。TRAIL的凋亡信号通路涉及TRAIL受体、具有死亡结构域的Fas相关蛋白（FADD）和半胱天冬酶-8。相比之下，TRAIL信号转导至NF-κ B的分子机制仍存在争议。在此，我们描述了TRAIL激活NF-κ B的受体近端介质。TRAIL受体1和2的DD缺失揭示其在NF-κ B信号传导中是必需的。因为FADD与TRAIL受体DD相互作用，所以测试FADD。在JURKAT T细胞白血病细胞中，RNAi介导的FADD或FADD缺陷的敲除减少或禁用TRAIL引起的NF-κ B信号传导。相反，TRAIL诱导的NF-κ B活化在受体相互作用蛋白1（RIP1）缺失或FLICE样抑制蛋白（FLIP）敲低后得以维持。外源性表达FADD可挽救TRAIL诱导的NF-κ B信号传导。TRAIL诱导的细胞凋亡所需的死亡效应结构域的RHDLL基序内的FADD功能缺失突变，消除了FADD募集caspase-8和介导NF-κ B活化的能力。因此，caspase-8的缺乏抑制了TRAIL诱导的NF-κ B的活化，这被野生型caspase-8所拯救，但不被催化失活的caspase-8突变体所拯救。这些数据确立了TRAIL诱导NF-κ B活化的机制，涉及TRAIL受体DD、FADD和caspase-8，但不涉及RIP1或FLIP。我们的研究结果表明，TRAIL诱导的细胞凋亡和NF-κ B的信号转导在caspase-8下游分叉。
Besides inducing apoptosis, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activates NF-κB. The apoptosis signaling pathway of TRAIL is well characterized involving TRAIL receptors, Fas-associated protein with death domain (FADD) and caspase-8. In contrast, the molecular mechanism of TRAIL signaling to NF-κB remains controversial. Here, we characterized the receptor–proximal mediators of NF-κB activation by TRAIL. Deletion of the DD of TRAIL receptors 1 and 2 revealed that it is essential in NF-κB signaling. Because FADD interacts with the TRAIL receptor DD, FADD was tested. RNAi-mediated knockdown of FADD or FADD deficiency in JURKAT T-cell leukemia cells decreased or disabled NF-κB signaling by TRAIL. In contrast, TRAIL-induced activation of NF-κB was maintained upon loss of receptor interacting protein 1 (RIP1) or knockdown of FLICE-like inhibitory protein (FLIP). Exogenous expression of FADD rescued TRAIL-induced NF-κB signaling. Loss-of-function mutations of FADD within the RHDLL motif of the death effector domain, which is required for TRAIL-induced apoptosis, abrogated FADD's ability to recruit caspase-8 and mediate NF-κB activation. Accordingly, deficiency of caspase-8 inhibited TRAIL-induced activation of NF-κB, which was rescued by wild-type caspase-8, but not by a catalytically inactive caspase-8 mutant. These data establish the mechanism of TRAIL-induced NF-κB activation involving the TRAIL receptor DD, FADD and caspase-8, but not RIP1 or FLIP. Our results show that signaling of TRAIL-induced apoptosis and NF-κB bifurcates downstream of caspase-8.
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