c-FLIPL is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis
c-FLIPL is a dual function regulator for caspase-8 activation and CD95-mediated apoptosis
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DOI：
10.1093/emboj/cdf356
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发表时间：
2002-07-15
期刊：
影响因子：
11.4
通讯作者：
Yang, XL
中科院分区：
文献类型：
--
作者：
Chang, DW;Xing, Z;Yang, XL
Caspase级联的激活是细胞凋亡的关键步骤，可以通过死亡适配器介导的启动子原天冬氨酸酶的同源寡聚化来实现。在这里，我们发现c-FLIPL是一种被广泛认为是一种凋亡抑制因子的缺乏蛋白酶的caspase同源物，它富含在CD95死亡诱导信号复合体(DISC)中，并通过异源二聚体有效地促进Proaspase-8的激活。C-FLIPL通过其蛋白酶样结构域发挥作用，该结构域有效地与原天冬氨酸蛋白酶-8结构域结合，并诱导酶原的酶活性。C-FLIPL在生理相关水平的异位表达促进CD95间盘中原天冬氨酸酶-8的处理并促进细胞凋亡，而c-FLIPL表达的降低则导致细胞凋亡的抑制。C-Flipl仅在高异位表达水平时作为细胞凋亡抑制因子发挥作用。因此，c-FLIPL定义了一种新型的caspase调节因子，它不同于死亡适配子，可以促进或抑制细胞凋亡。
Activation of the caspase cascade is a pivotal step in apoptosis and can occur via death adaptor-mediated homo-oligomerization of initiator procaspases. Here we show that c-FLIPL, a protease-deficient caspase homolog widely regarded as an apoptosis inhibitor, is enriched in the CD95 death-inducing signaling complex (DISC) and potently promotes procaspase-8 activation through hetero-dimerization. c-FLIPL exerts its effect through its protease-like domain, which associates efficiently with the procaspase-8 protease domain and induces the enzymatic activity of the zymogen. Ectopic expression of c-FLIPL at physiologically relevant levels enhances procaspase-8 processing in the CD95 DISC and promotes apoptosis, while a decrease of c-FLIPL expression results in inhibition of apoptosis. c-FLIPL acts as an apoptosis inhibitor only at high ectopic expression levels. Thus, c-FLIPL defines a novel type of caspase regulator, distinct from the death adaptors, that can either promote or inhibit apoptosis.