Cullin3-Based Polyubiquitination and p62-Dependent Aggregation of Caspase-8 Mediate Extrinsic Apoptosis Signaling
Cullin3-Based Polyubiquitination and p62-Dependent Aggregation of Caspase-8 Mediate Extrinsic Apoptosis Signaling
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DOI：
10.1016/j.cell.2009.03.015
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发表时间：
2009-05-15
期刊：
影响因子：
64.5
通讯作者：
Ashkenazi, Avi
中科院分区：
文献类型：
--
作者：
Jin, Zhaoyu;Li, Yun;Ashkenazi, Avi
细胞表面死亡受体如DR 4和DR 5通过死亡诱导信号复合物（DISC）触发细胞凋亡，该复合物募集顶端蛋白酶胱天蛋白酶-8。凋亡的承诺需要有效的激活和自催化释放的caspase-8进入细胞质，从事刽子手caspase。虽然DISC募集启动半胱天冬酶-8刺激，但蛋白酶的完全激活取决于尚未完全理解的进一步分子聚集事件。在这里，我们表明，死亡受体连接诱导caspase-8的聚泛素化，通过一个以前未知的相互作用的DISC与cullin 3（CUL 3）为基础的E3连接酶。CUL 3介导的caspase-8多聚泛素化需要RING盒蛋白RBX 1，而去泛素化酶A20逆转了这种修饰。泛素结合蛋白p62/螯合体-1促进了CUL 3修饰的caspase-8在p62依赖性病灶内的聚集，导致酶的完全激活和加工，并驱动细胞死亡。这些结果确定了一种机制，积极控制细胞凋亡信号的多聚泛素化和聚集的一个关键启动caspase。
Cell-surface death receptors such as DR4 and DR5 trigger apoptosis through a death-inducing signaling complex (DISC) that recruits the apical protease caspase-8. Apoptosis commitment requires efficient activation and autocatalytic release of caspase-8 into the cytoplasm to engage executioner caspases. While DISC recruitment initiates caspase-8 stimulation, full activation of the protease depends on further molecular aggregation events that are not fully understood. Here, we show that death receptor ligation induces polyubiquitination of caspase-8, through a previously unknown interaction of the DISC with a cullin3 (CUL3)-based E3 ligase. CUL3-mediated caspase-8 polyubiquitination required the RING box protein RBX1, whereas the deubiquitinase A20 reversed this modification. The ubiquitin-binding protein p62/sequestosome-1 promoted aggregation of CUL3-modified caspase-8 within p62-dependent foci, leading to full activation and processing of the enzyme and driving commitment to cell death. These results identify a mechanism that positively controls apoptosis signaling by polyubiquitination and aggregation of a key initiator caspase.