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.

中文翻译：

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NUMB 通过抑制 NOTCH1 胞内结构域的泛素化来增强 Notch 信号传导。


Notch 受体 (NICD) 胞内结构域的释放和核转位是 Notch 信号介导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，我们令人惊讶地发现 NUMB 蛋白通过调节泛素-蛋白酶体机制来稳定 NOTCH1 受体 (N1ICD) 的胞内结构域，这与 NUMB 在调节内吞作用中的作用无关。 BAP1 是一种去泛素化酶 (DUB)，被进一步鉴定为 N1ICD 的正调节因子，NUMB 促进 N1ICD 和 BAP1 之间的关联以稳定 N1ICD。有趣的是，BAP1 独立于 DUB 活性但依赖于 BRCA1 抑制功能来稳定 N1ICD。 BAP1 增强 Notch 信号传导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 信号传导。