FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity.
FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity.
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DOI：
10.1042/bj20101738
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发表时间：
2011-02-01
期刊：
影响因子：
--
通讯作者：
Salvesen GS
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文献类型：
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作者：
Pop C;Oberst A;Drag M;Van Raam BJ;Riedl SJ;Green DR;Salvesen GS
半胱天冬酶-8是由死亡受体激活以启动细胞凋亡的外源性途径的引发剂半胱天冬酶。半胱天冬酶-8活化涉及半胱天冬酶-8酶原的二聚化和随后的结构域间自动加工，并且最近发表的工作已经确定，半胱天冬酶-8的自动加工位点的消除废除其促凋亡功能，同时使其增殖功能保持完整。观察到缺乏二聚化衔接子FADD或胱天蛋白酶partial FLIPL的小鼠共享胱天蛋白酶-8缺陷小鼠的发育异常，这导致了这样的假设，即胱天蛋白酶-8和FLIPL之间的异二聚体的FADD依赖性形成可以介导胱天蛋白酶-8的发育作用。使用诱导型二聚化系统，我们证明，裂解的催化结构域的胱天蛋白酶-8的激活同源二聚化的情况下，其活性是至关重要的。然而，我们发现FLIPL作为caspase-8在二聚化诱导的活化中的伴侣的使用拯救了两种原聚体中亚基间接头蛋白水解的需要。此外，在加工之前，与FLIPL复合的半胱天冬酶-8不产生完全活性的酶，而是能够加工仅选择的天然底物的减毒物质。基于这些结果，我们提出了一种机制，在FLIPL的存在下，通过二聚化的caspase-8激活，以及凋亡和非凋亡途径中的caspase-8功能分歧的机制。
Caspase-8 is an initiator caspase that is activated by death receptors to initiate the extrinsic pathway of apoptosis. Caspase-8 activation involves dimerization and subsequent interdomain autoprocessing of caspase-8 zymogens, and recently published work has established that elimination of the autoprocessing site of caspase-8 abrogates its pro-apoptotic function while leaving its proliferative function intact. The observation that the developmental abnormalities of caspase-8 deficient mice are shared by mice lacking the dimerization adapter FADD or the caspase paralog FLIPL has led to the hypothesis that FADD-dependent formation of heterodimers between caspase-8 and FLIPL could mediate the developmental role of caspase-8. Using an inducible dimerization system we demonstrate that cleavage of the catalytic domain of caspase-8 is crucial for its activity in the context of activation by homodimerization. However, we find that use of FLIPL as a partner for caspase-8 in dimerization-induced activation rescues the requirement for intersubunit linker proteolysis in both protomers. Moreover, before processing, caspase-8 in complex with FLIPL does not generate a fully active enzyme, but an attenuated species able to process only select natural substrates. Based on these results we propose a mechanism of caspase-8 activation by dimerization in the presence of FLIPL, as well as a mechanism of caspase-8 functional divergence in apoptotic and non-apoptotic pathways.