NUMB enhances Notch signaling by repressing ubiquitination of NOTCH1 intracellular domain
NUMB enhances Notch signaling by repressing ubiquitination of NOTCH1 intracellular domain
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NUMB 通过抑制 NOTCH 胞内结构域的泛素化来增强 Notch 信号传导
DOI：
10.1093/jmcb/mjz088
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发表时间：
2020-05-01
影响因子：
5.5
通讯作者：
Zhou, Yan
中科院分区：
文献类型：
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作者：
Luo, Zhiyuan;Mu, Lili;Zhou, Yan
Notch受体胞内结构域（NICD）的释放和核转位是Notch信号介导的转录激活的先决条件。NICD经历各种翻译后修饰，包括泛素化。在这里，我们惊讶地发现，NUMB蛋白稳定NOTCH 1受体（N1 ICD）的细胞内结构域通过调节泛素蛋白酶体机制，这是独立的NUMB的作用，在调节内吞作用。BAP 1是一种去泛素化酶（DUB），被进一步鉴定为N1 ICD的正调节剂，NUMB促进N1 ICD和BAP 1之间的结合以稳定N1 ICD。有趣的是，BAP 1稳定N1 ICD独立于其DUB活性，但依赖于BRCA 1抑制功能。BAP 1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BAP 1-BRCA 1复合物的泛素化活性来增强Notch信号传导。
The release and nuclear translocation of the intracellular domain of Notch receptor (NICD) is the prerequisite for Notch signalingmediated 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 ubiquitinproteasome 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.