Ubiquitylation is required for the incorporation of the Notch receptor into intraluminal vesicles to prevent prolonged and ligand-independent activation of the pathway.
Ubiquitylation is required for the incorporation of the Notch receptor into intraluminal vesicles to prevent prolonged and ligand-independent activation of the pathway.
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DOI：
10.1186/s12915-022-01245-y
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发表时间：
2022-03-10
期刊：
影响因子：
5.4
通讯作者：
Klein T
中科院分区：
文献类型：
--
作者：
Schnute B;Shimizu H;Lyga M;Baron M;Klein T
配体和受体的泛素化在调节进化上保守的Notch信号通路的活性中起重要作用。然而，尽管鉴定了几种致力于受体的E3连接酶，但其激活Notch的功能尚未完全了解。在这里，我们分析了Notch受体的变体，其中其细胞内结构域中的所有赖氨酸被精氨酸取代。我们对这种变体的分析表明，Notch的泛素化对其内吞作用不是必需的。我们确定了Notch受体中赖氨酸泛素化的两个功能。首先，它是细胞核中游离Notch胞内结构域（NICD）降解所必需的，这阻止了该途径的长期激活。更重要的是，它也是Notch掺入成熟内体的管腔内囊泡以防止晚期内体隔室的途径的配体非依赖性激活所必需的。这些发现阐明了Notch受体的赖氨酸依赖性泛素化的作用，并表明Notch被几种独立的操作机制内吞。在线版本包含补充材料，可通过10.1186/s12915-022-01245-y获得。
Ubiquitylation of the ligands and the receptor plays an important part in the regulation of the activity of the evolutionary conserved Notch signalling pathway. However, its function for activation of Notch is not completely understood, despite the identification of several E3 ligases devoted to the receptor. Here we analysed a variant of the Notch receptor where all lysines in its intracellular domain are replaced by arginines. Our analysis of this variant revealed that ubiquitylation of Notch is not essential for its endocytosis. We identified two functions for ubiquitylation of lysines in the Notch receptor. First, it is required for the degradation of free Notch intracellular domain (NICD) in the nucleus, which prevents a prolonged activation of the pathway. More importantly, it is also required for the incorporation of Notch into intraluminal vesicles of maturing endosomes to prevent ligand-independent activation of the pathway from late endosomal compartments. The findings clarify the role of lysine-dependent ubiquitylation of the Notch receptor and indicate that Notch is endocytosed by several independent operating mechanisms. The online version contains supplementary material available at 10.1186/s12915-022-01245-y.
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影响因子：
11.8
作者：
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通讯作者：
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影响因子：
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DOI：
10.1083/jcb.201411001
发表时间：
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期刊：
The Journal of cell biology
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