Nuclear factor-κB-inducible death effector domain-containing protein suppresses tumor necrosis factor-mediated apoptosis by inhibiting caspase-8 activity
Nuclear factor-κB-inducible death effector domain-containing protein suppresses tumor necrosis factor-mediated apoptosis by inhibiting caspase-8 activity
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DOI：
10.1074/jbc.m102464200
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发表时间：
2001-07-13
影响因子：
4.8
通讯作者：
Wang, CY
中科院分区：
文献类型：
--
作者：
You, ZB;Ouyang, H;Wang, CY
转录因子核因子- kappab （NF-kappaB）的激活在抑制肿瘤坏死因子（TNF）介导的细胞凋亡中起重要作用，NF-kappaB调节多种抗凋亡分子，包括细胞凋亡抑制剂、Bcl-2家族蛋白（A1和Bcl-X-L）和IEX-IL。在这里，我们报道了含有小死亡效应域（DEI）的蛋白NDED （NF-kappaB诱导的含ed蛋白）的表达依赖于NF-kappaB的激活，NF-kappaB的天然抑制剂IKB α抑制NF-kappaB，抑制TNF诱导的NDED mRNA表达，NF-kappaB缺失细胞中NDED的恢复抑制TNF诱导的凋亡，有趣的是，与caspase-8抑制剂细胞fadd样白细胞介素-1 β转换酶抑制蛋白（c-FLIP）不同，NDED通过抑制tnf诱导的caspase-8酶活性而非caspase-8加工来抑制tnf介导的细胞凋亡。此外，NDED不能抑制依托oposide介导的不依赖于caspase-8活化的细胞凋亡。我们的研究结果首次证明了NF-kappaB通过抑制caspase-8活性转录诱导含ed蛋白抑制tnf介导的细胞凋亡，这为NF-kappaB的抗凋亡机制提供了新的见解。
Activation of the transcription factor nuclear factor-kappaB (NF-kappaB) has been found to play an essential role in the inhibition of tumor necrosis factor (TNF)-mediated apoptosis, NF-kappaB regulates several antiapoptotic molecules including inhibitors of apoptosis, Bcl-2 family proteins (A1 and Bcl-X-L) and IEX-IL. Here we report that the expression of a small death effector domain (DEI)-containing protein, NDED (NF-kappaB-inducible DED-containing protein), depends on the activation of NF-kappaB, The inhibition of NF-kappaB by IKB alpha a natural inhibitor of NF-kappaB, suppressed NDED mRNA expression induced by TNF, The restoration of NDED in NF-kappaB null cells inhibited TNF-induced apoptosis, Intriguingly, unlike the caspase-8 inhibitor cellular FADD-like interleukin-1 beta converting enzyme-inhibitory protein (c-FLIP), NDED suppressed TNF-mediated apoptosis by inhibiting TNF-induced caspase-8 enzymatic activity but not the processing of caspase-8, Furthermore, NDED could not inhibit etoposide-mediated apoptosis that is independent of caspase-8 activation. Our results provide the first demonstration that NF-kappaB transcriptionally induces the DED-containing protein to suppress TNF-mediated apoptosis by inhibiting caspase-8 activity, which offers new insight into the antiapoptotic mechanism of NF-kappaB.