Drosophila epsin mediates a select endocytic pathway that DSL ligands must enter to activate notch
Drosophila epsin mediates a select endocytic pathway that DSL ligands must enter to activate notch
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DOI：
10.1242/dev.01413
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发表时间：
2004-11-01
期刊：
影响因子：
4.6
通讯作者：
Struhl, G
中科院分区：
文献类型：
--
作者：
Wang, WD;Struhl, G
最近的研究结果表明，Delta/Serrate/Lag2 （DSL）信号通过一种前所未有的机制激活Notch，这种机制需要配体在信号发送细胞中被内吞，从而激活信号接收细胞中的受体。在这里，我们发现缺乏Epsin（一种用于网格蛋白介导的内吞作用的保守接头蛋白）的细胞除了不能发送DSL信号外，行为正常。令人惊讶的是，我们发现Epsin并不需要DSL蛋白的大量内吞作用。相反，Epsin似乎是将DSL蛋白靶向到一个特殊的内吞途径所必需的，它们必须进入这个途径才能获得信号活性。我们提出的证据表明，DSL蛋白必须是单泛素化的，才能被Epsin靶向到这一途径。此外，我们表明，通过引入介导低密度脂蛋白（LDL）受体内吞和再循环的内化信号，可以绕过Epsin和单泛素化的要求。我们认为Epsin对DSL信号传导至关重要，因为它将单泛素化的DSL蛋白靶向到一个内吞循环室，它们必须进入这个循环室才能转化为活性配体。或者，可能需要Epsin将单泛素化的DSL蛋白靶向到具有Notch激活所必需的特殊性质的包被凹坑的特定亚类。
Recent findings suggest that Delta/Serrate/Lag2 (DSL) signals activate Notch by an unprecedented mechanism that requires the ligands to be endocytosed in signalsending cells to activate the receptor in signal-receiving cells. Here, we show that cells devoid of Epsin, a conserved adaptor protein for Clathrin-mediated endocytosis, behave normally except that they cannot send DSL signals. Surprisingly, we find that Epsin is not required for bulk endocytosis of DSL proteins. Instead, Epsin appears to be essential for targeting DSL proteins to a special endocytic pathway that they must enter to acquire signaling activity. We present evidence that DSL proteins must be monoubiquitinated to be targeted by Epsin to this pathway. Furthermore, we show that the requirements for both Epsin and mono-ubiquitination can be bypassed by introducing the internalization signal that mediates endocytosis and recycling of the Low Density Lipoprotein (LDL) receptor. We propose that Epsin is essential for DSL signaling because it targets mono-ubiquitinated DSL proteins to an endocytic recycling compartment that they must enter to be converted into active ligands. Alternatively Epsin may be required to target monoubiquitinated DSL proteins to a particular subclass of coated pits that have special properties essential for Notch activation.