Institute of Genetics, Heinrich-Heine-Universitaet Duesseldorf, Duesseldorf, Germany.
Molekulare Zellbiologie, Institut I für Anatomie, Uniklinik Köln, Universität zu Köln, Köln, Germany.
Elife. 2017 Sep 29;6:e27346. doi: 10.7554/eLife.27346.
Ubiquitylation (ubi) by the E3-ligases Mindbomb1 (Mib1) and Neuralized (Neur) is required for activation of the DSL ligands Delta (Dl) and Serrate (Ser) to activate Notch signalling. These ligases transfer ubiquitin to lysines of the ligands' intracellular domains (ICDs), which sends them into an Epsin-dependent endocytic pathway. Here, we have tested the requirement of ubi of Dl for signalling. We found that Dl requires ubi for its full function, but can also signal in two ubi-independent modes, one dependent and one independent of Neur. We identified two neural lateral specification processes where Dl signals in an ubi-independent manner. Neur, which is needed for these processes, was shown to be able to activate Dl in an ubi-independent manner. Our analysis suggests that one important role of DSL protein ubi by Mib1 is their release from cis-inhibitory interactions with Notch, enabling them to trans-activate Notch on adjacent cells.
泛素化（ubi）由 E3 连接酶 Mindbomb1（Mib1）和 Neuralized（Neur）完成，这对于激活 DSL 配体 Delta（Dl）和 Serrate（Ser）以激活 Notch 信号转导是必需的。这些连接酶将泛素转移到配体细胞内结构域（ICD）的赖氨酸上，从而将它们送入 Epsin 依赖性内吞途径。在这里，我们已经测试了 Dl 信号所需要的 ubi。我们发现 Dl 发挥其全部功能需要 ubi，但也可以通过两种 ubi 非依赖的模式进行信号转导，一种依赖 Neur，另一种不依赖 Neur。我们确定了 Dl 以 ubi 非依赖方式进行信号转导的两个神经侧向特化过程。对于这些过程，需要 Neur 来激活 Dl 的 ubi 非依赖性。我们的分析表明，Mib1 对 DSL 蛋白 ubi 的一个重要作用是将它们从与 Notch 的顺式抑制相互作用中释放出来，从而使它们能够在相邻细胞上 trans-activate Notch。
