College of Life Sciences, Renmin Hospital of Wuhan University, Medical Research Institute at School of Medicine, Wuhan University, Wuhan 430072, China.
J Mol Cell Biol. 2020 Jun 11;12(5):345-358. doi: 10.1093/jmcb/mjz088.
The release and nuclear translocation of the intracellular domain of Notch receptor (NICD) is the prerequisite for Notch signaling-mediated transcriptional activation. NICD is subjected to various posttranslational modifications including ubiquitination. Here, we surprisingly found that NUMB proteins stabilize the intracellular domain of NOTCH1 receptor (N1ICD) by regulating the ubiquitin-proteasome machinery, which is independent of NUMB's role in modulating endocytosis. BAP1, a deubiquitinating enzyme (DUB), was further identified as a positive N1ICD regulator, and NUMB facilitates the association between N1ICD and BAP1 to stabilize N1ICD. Intriguingly, BAP1 stabilizes N1ICD independent of its DUB activity but relying on the BRCA1-inhibiting function. BAP1 strengthens Notch signaling and maintains stem-like properties of cortical neural progenitor cells. Thus, NUMB enhances Notch signaling by regulating the ubiquitinating activity of the BAP1-BRCA1 complex.
Notch 受体（NICD）的细胞内结构域的释放和核易位是 Notch 信号介导的转录激活的先决条件。NICD 受到各种翻译后修饰，包括泛素化。在这里，我们惊讶地发现 NUMB 蛋白通过调节泛素蛋白酶体机制稳定 NOTCH1 受体（N1ICD）的细胞内结构域，这独立于 NUMB 在调节内吞作用中的作用。BAP1，一种去泛素化酶（DUB），被进一步鉴定为 N1ICD 的正调控因子，NUMB 促进 N1ICD 与 BAP1 之间的关联，从而稳定 N1ICD。有趣的是，BAP1 稳定 N1ICD 不依赖于其 DUB 活性，而是依赖于 BRCA1 抑制功能。BAP1 增强 Notch 信号并维持皮质神经祖细胞的干细胞样特性。因此，NUMB 通过调节 BAP1-BRCA1 复合物的泛素化活性来增强 Notch 信号。
