The long form of FLIP is an activator of caspase-8 at the fas death-inducing signaling complex
The long form of FLIP is an activator of caspase-8 at the fas death-inducing signaling complex
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DOI：
10.1074/jbc.m206882200
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发表时间：
2002-11-22
影响因子：
4.8
通讯作者：
Grütter, MG
中科院分区：
文献类型：
--
作者：
Micheau, O;Thome, M;Grütter, MG
死亡受体，例如 Fas 和肿瘤坏死因子相关的凋亡诱导配体受体，募集 Fas 相关的死亡结构域和 pro-caspase-8 同二聚体，然后被自蛋白水解激活。活性 caspase-8 被释放到细胞质中，在细胞质中裂解包括 pro-caspase-3 在内的各种蛋白质，导致细胞凋亡。细胞 Fas 相关死亡结构域样白细胞介素 1-β 转换酶抑制蛋白长型 (FLIPL) 是 caspase-8 的结构同源物，由于活性位点的多个突变而缺乏 caspase 活性，是死亡受体诱导的细胞凋亡的有效抑制剂。 FLIPL 被提议通过与 caspase-8 形成活性异二聚体来阻断 caspase-8 活性。相比之下，我们认为 FLPLL 结合的 caspase-8 是一种活性蛋白酶。异质复合物形成后，会发生有限的 caspase-8 自动加工，导致 p43/41 和 p12 亚基的生成。这种部分加工的形式以及未切割的 FLIPL-caspase-8 杂复合物都具有蛋白水解活性，因为它们都能有效结合合成底物。此外，FLIPL 表达有利于 Fas 信号复合物内的受体相互作用激酶 (RIP) 加工。我们认为 FLIPL 抑制 caspase-8 释放依赖性促凋亡信号，而 FLIPL-caspase-8 杂复合物的单一膜限制活性位点具有蛋白水解活性，并作用于 RIP 等局部底物。
Death receptors, such as Fas and tumor necrosis factor-related apoptosis-inducing ligand receptors, recruit Fas-associated death domain and pro-caspase-8 homodimers, which are then autoproteolytically activated. Active caspase-8 is released into the cytoplasm, where it cleaves various proteins including pro-caspase-3, resulting in apoptosis. The cellular Fas-associated death domain-like interleukin-1-beta-converting enzyme-inhibitory protein long form (FLIPL), a structural homologue of caspase-8 lacking caspase activity because of several mutations in the active site, is a potent inhibitor of death receptor-induced apoptosis. FLIPL is proposed to block caspase-8 activity by forming a proteolytically in active heterodimer with caspase-8. In contrast, we propose that FLPLL-bound caspase-8 is an active protease. Upon heterocomplex formation, a limited caspase-8 autoprocessing occurs resulting in the generation of the p43/41 and the p12 subunits. This partially processed form but also the non-cleaved FLIPL-caspase-8 heterocomplex are proteolytically active because they both bind synthetic substrates efficiently. Moreover, FLIPL expression favors receptor-interacting kinase (RIP) processing within the Fas-signaling complex. We propose that FLIPL inhibits caspase-8 release-dependent pro-apoptotic signals, whereas the single, membrane-restricted active site of the FLIPL-caspase-8 heterocomplex is proteolytically active and acts on local substrates such as RIP.