Deubiquitinase USP10 regulates Notch signaling in the endothelium
Deubiquitinase USP10 regulates Notch signaling in the endothelium
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DOI：
10.1126/science.aat0778
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发表时间：
2019-04-12
期刊：
影响因子：
56.9
通讯作者：
Potente, M.
中科院分区：
文献类型：
--
作者：
Lim, R.;Sugino, T.;Potente, M.
Notch信号是血管形态发生的核心模式模块，共同决定内皮细胞（ECs）的出芽行为。Notch活性的严格定量和时间控制对于血管发育是必不可少的，但内皮细胞中Notch调节的细节尚不完全清楚。我们发现，泛素特异性肽酶10（USP 10）与NOTCH 1胞内结构域（NICD 1）相互作用，以减缓这种短寿命形式的活化NOTCH 1受体的泛素依赖性周转。因此，USP10的失活降低了NICD 1的丰度和稳定性，并减少了Notch诱导的靶基因在EC中的表达。在小鼠中，内皮Usp 10的缺失增加了血管发芽，并部分恢复了由NICD 1异位表达引起的图案缺陷。因此，USP10作为NICD 1去泛素化酶发挥功能，在血管生成发芽期间微调内皮Notch反应。
Notch signaling is a core patterning module for vascular morphogenesis that codetermines the sprouting behavior of endothelial cells (ECs). Tight quantitative and temporal control of Notch activity is essential for vascular development, yet the details of Notch regulation in ECs are incompletely understood. We found that ubiquitin-specific peptidase 10 (USP10) interacted with the NOTCH1 intracellular domain (NICD1) to slow the ubiquitin-dependent turnover of this short-lived form of the activated NOTCH1 receptor. Accordingly, inactivation of USP10 reduced NICD1 abundance and stability and diminished Notch-induced target gene expression in ECs. In mice, the loss of endothelial Usp10 increased vessel sprouting and partially restored the patterning defects caused by ectopic expression of NICD1. Thus, USP10 functions as an NICD1 deubiquitinase that fine-tunes endothelial Notch responses during angiogenic sprouting.