Death-receptor activation halts clathrin-dependent endocytosis
Death-receptor activation halts clathrin-dependent endocytosis
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DOI：
10.1073/pnas.0604044103
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发表时间：
2006-07-05
影响因子：
11.1
通讯作者：
Ashkenazi, Avi
中科院分区：
文献类型：
--
作者：
Austin, Cary D.;Lawrence, David A.;Ashkenazi, Avi
内吞作用对于细胞稳态的各个方面都是至关重要的。在这里，我们表明，促凋亡死亡受体（DR）触发网格蛋白依赖的内吞机制的选择性破坏。DR刺激诱导快速，半胱天冬酶介导的裂解的关键网格蛋白途径的组成部分，停止细胞摄取的经典货物蛋白转铁蛋白。DR-近端启动子半胱天冬酶在功能不同的结构域之间切割网格蛋白衔接子亚基AP 2 α，而效应子半胱天冬酶处理网格蛋白的重链。DR 5经历配体诱导的网格蛋白介导的内吞作用，表明DR信号复合物的内化促进了半胱天冬酶靶向网格蛋白途径。内吞阻断，温度敏感的发动蛋白-1突变体衰减DR内化，增强DR下游的半胱天冬酶刺激，并增加凋亡。因此，DR触发的半胱天冬酶活性破坏网格蛋白依赖性内吞作用，导致程序性细胞死亡的放大。
Endocytosis is crucial for various aspects of cell homeostasis. Here, we show that proapoptotic death receptors (DRs) trigger selective destruction of the clathrin-dependent endocytosis machinery. DR stimulation induced rapid, caspase-mediated cleavage of key clathrin-pathway components, halting cellular uptake of the classic cargo protein transferrin. DR-proximal initiator caspases cleaved the clathrin adaptor subunit AP2 alpha between functionally distinct domains, whereas effector caspases processed clathrin's heavy chain. DR5 underwent ligand-induced, clathrin-mediated endocytosis, suggesting that internalization of DR signaling complexes facilitates clathrin-pathway targeting by caspases. An endocytosis-blocking, temperature-sensitive dynamin-1 mutant attenuated DR internalization, enhanced caspase stimulation downstream of DRs, and increased apoptosis. Thus, DR-triggered caspase activity disrupts clathrin-dependent endocytosis, leading to amplification of programmed cell death.