Activation of Notch in lgd mutant cells requires the fusion of late endosomes with the lysosome
Activation of Notch in lgd mutant cells requires the fusion of late endosomes with the lysosome
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DOI：
10.1242/jcs.116590
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发表时间：
2013-01-15
影响因子：
4
通讯作者：
Klein, Thomas
中科院分区：
文献类型：
--
作者：
Schneider, Markus;Troost, Tobias;Klein, Thomas
肿瘤抑制因子Lethal（2）giant discs（Lgd）是果蝇中Notch信号受体以及其他跨膜蛋白的内体运输的调节剂。其功能的丧失导致Notch信号传导受体的不受控制的配体非依赖性激活。在这里，我们研究了lgd功能丧失的后果和Notch激活的要求。我们发现，在lgd细胞中的Notch的激活是独立的Kuz和依赖于c-分泌酶。我们发现lgd细胞有一个缺陷，它延迟了跨膜蛋白的降解，跨膜蛋白是质膜上的居民。此外，我们的结果表明，在lgd细胞中Notch的激活发生在溶酶体中。相比之下，该途径在编码ESCRT-III组分Shrub的基因突变体的早期阶段被激活，Shrub是Lgd的相互作用伴侣。我们进一步表明，Notch的激活似乎是lgd功能丧失的一般后果。此外，lgd细胞的电子显微镜显示，它们含有扩大的多泡体。所呈现的结果进一步阐明了在脱轨的内吞作用后不受控制的Notch激活的机制。
The tumour suppressor Lethal (2) giant discs (Lgd) is a regulator of endosomal trafficking of the Notch signalling receptor as well as other transmembrane proteins in Drosophila. The loss of its function results in an uncontrolled ligand-independent activation of the Notch signalling receptor. Here, we investigated the consequences of loss of lgd function and the requirements for the activation of Notch. We show that the activation of Notch in lgd cells is independent of Kuz and dependent on c-secretase. We found that the lgd cells have a defect that delays degradation of transmembrane proteins, which are residents of the plasma membrane. Furthermore, our results show that the activation of Notch in lgd cells occurs in the lysosome. By contrast, the pathway is activated at an earlier phase in mutants of the gene that encodes the ESCRT-III component Shrub, which is an interaction partner of Lgd. We further show that activation of Notch appears to be a general consequence of loss of lgd function. In addition, electron microscopy of lgd cells revealed that they contain enlarged multi-vesicular bodies. The presented results further elucidate the mechanism of uncontrolled Notch activation upon derailed endocytosis.