Regulation of the Drosophila apoptosome through feedback inhibition.
Regulation of the Drosophila apoptosome through feedback inhibition.
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DOI：
10.1038/ncb1803
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发表时间：
2008-12
影响因子：
21.3
通讯作者：
Ryoo, Hyung Don
中科院分区：
文献类型：
--
作者：
Shapiro, Peter J.;Hsu, Hans H.;Jung, Heekyung;Robbins, Edith S.;Ryoo, Hyung Don
细胞凋亡由半胱氨酸蛋白酶家族的成员半胱氨酸蛋白酶诱导。半胱天冬酶是作为无活性的酶原合成的，并且起始半胱天冬酶首先通过与其衔接蛋白的寡聚复合物（如寡聚体）缔合而获得活性。激活的起始半胱天冬酶随后切割并激活效应半胱天冬酶。虽然这样的蛋白水解级联将预测少量活性半胱天冬酶可以不可逆地放大半胱天冬酶活性并触发细胞凋亡，但许多细胞可以维持中等水平的半胱天冬酶活性以在细胞分化、形状改变和迁移中发挥非细胞凋亡作用。在这里，我们表明，果蝇的线粒体参与反馈抑制回路，从而调节其在体内的激活水平。具体而言，衔接蛋白Apaf-1降低了其相关的起始剂胱天蛋白酶Dronc的水平，而不触发细胞凋亡。相反，Dronc降低Apaf-1蛋白水平。这种相互抑制依赖于Dronc的催化位点和Apaf-1内的半胱天冬酶切割位点。此外，果蝇凋亡蛋白抑制剂1（Diap 1）是这一过程所必需的。我们推测，这种反馈抑制允许细胞调节凋亡和非凋亡目的的半胱天冬酶激活程度。
Apoptosis is induced by caspases, which are members of the cysteine protease family. Caspases are synthesized as inactive zymogens and initiator caspases first gain activity by associating with an oligomeric complex of their adaptor proteins, such as the apoptosome. Activated initiator caspases subsequently cleave and activate effector caspases. While such a proteolytic cascade would predict that a small number of active caspases could irreversibly amplify caspase activity and trigger apoptosis, many cells can maintain moderate levels of caspase activity to perform non-apoptotic roles in cellular differentiation, shape change and migration. Here we show that the Drosophila apoptosome engages in a feedback inhibitory loop, thereby moderating its activation level in vivo. Specifically, the adaptor protein Apaf-1 lowers the level of its associated initiator caspase, Dronc, without triggering apoptosis. Conversely, Dronc lowers Apaf-1 protein levels. This mutual suppression depends upon Dronc’s catalytic site and a caspase cleavage site within Apaf-1. Moreover, the Drosophila Inhibitor of Apoptosis Protein 1 (Diap1) is required for this process. We speculate that this feedback inhibition allows cells to regulate the degree of caspase activation for apoptotic and non-apoptotic purposes.
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影响因子：
12.4
作者：
Herman-Bachinsky, Y.;Ryoo, H. -D.;Gonen, H.
通讯作者：
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