N-terminal fragment of c-FLIP(L) processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-κB signaling pathway
N-terminal fragment of c-FLIP(L) processed by caspase 8 specifically interacts with TRAF2 and induces activation of the NF-κB signaling pathway
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DOI：
10.1128/mcb.24.7.2627-2636.2004
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发表时间：
2004-04-01
影响因子：
5.3
通讯作者：
Tschopp, J
中科院分区：
文献类型：
--
作者：
Kataoka, T;Tschopp, J
Caspase 8不仅是死亡受体介导的细胞凋亡所必需的，也是免疫系统中淋巴细胞活化所必需的。c-FLIP的长剪接形式FLIP(L)是caspase 8的特异性底物之一，FLIP(L)的表达增加可促进NF-kappaB信号通路的激活。合成的caspase抑制剂benzyloxycarbonyl-Val-Ala-Asp(OMe)- fluorom甲基酮（zVAD-fmk）可显著阻断FLIP过表达诱导的NF-kappaB活化(L)。FLIP(L)被caspase 8特异性加工成n端FLIP（p43）和c端FLIP（p12）。只有FLIP（p43）能够像FLIP(L)一样有效地诱导NF-kappaB激活，并且FLIP（p43）诱导的NF-kappaB激活对zad -fmk不敏感。在caspase 8缺失的细胞中，只有当procaspase 8或caspase 8（p43）被补充时，FLIP（p43）才会激活NF-kappaB。FLIP（p43）诱导的NF-kappaB激活被显性阴性TRAF2严重阻断。此外，内源性TRAF2与FLIP（p43）特异性相互作用，FLIP(p43) -caspase 8-TRAF2三级复合物的形成是诱导NF-kappaB活化的先决条件。WAD-fink阻止TRAF2进入诱导死亡的信号复合体。因此，我们目前的研究结果表明，caspase 8处理的FLIP（p43）特异性地与TRAF2相互作用，随后诱导NF-kappaB信号通路的激活。
Caspase 8 is required not only for death receptor-mediated apoptosis but also for lymphocyte activation in the immune system. FLIP(L), the long-splice form of c-FLIP, is one of the specific substrates for caspase 8, and increased expression of FLIP(L) promotes activation of the NF-kappaB signaling pathway. The synthetic caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) markedly blocked NF-kappaB activation induced by overexpression of FLIP(L). FLIP(L) is specifically processed by caspase 8 into N-terminal FLIP(p43) and C-terminal FLIP(p12). Only FLIP(p43) was able to induce NF-kappaB activation as efficiently as FLIP(L), and FLIP(p43) -induced NF-kappaB activation became insensitive to zVAD-fmk. In caspase 8-deficient cells, FLIP(p43) provoked NF-kappaB activation only when procaspase 8 or caspase 8(p43) was complemented. FLIP(p43) -induced NF-kappaB activation was profoundly blocked by the dominant-negative TRAF2. Moreover, endogenous TRAF2 interacted specifically with FLIP(p43), and the formation of the FLIP (p43) -caspase 8-TRAF2 tertiary complex was a prerequisite to induction of NF-kappaB activation. WAD-fink prevented the recruitment of TRAF2 into the death-inducing signaling complex. Thus, our present results demonstrate that FLIP(p43) processed by caspase 8 specifically interacts with TRAF2 and subsequently induces activation of the NF-kappaB signaling pathway.