Shear stress activates ADAM10 sheddase to regulate Notch1 via the Piezo1 force sensor in endothelial cells
Shear stress activates ADAM10 sheddase to regulate Notch1 via the Piezo1 force sensor in endothelial cells
复制标题
DOI：
10.7554/elife.50684
复制
发表时间：
2020-06-02
期刊：
影响因子：
7.7
通讯作者：
Beech, David J.
中科院分区：
文献类型：
--
作者：
Caolo, Vincenza;Debant, Marjolaine;Beech, David J.
机械力是Notch信号的决定因素，但力检测的机制及其与Notch的耦合尚不清楚。我们提出了Piezo1通道的作用，它是机械激活的非选择性阳离子通道。在培养的微血管内皮细胞中，切应力或化学激动剂Yoda1激活的Piezo1通道激活了去整合素和金属蛋白酶结构域包含蛋白10(ADAM10)，ADAM10是一种受钙离子调节的跨膜脱落酶，介导了S2 Notch1的切割。与这一观察结果一致，我们发现依赖于Piezo1的Notch1胞内域(NICD)的丰度增加，这依赖于ADAM10和下游的S3裂解酶，即伽马分泌酶。在成年小鼠中，有条件的内皮特异性破坏Piezo1抑制了肝血管中多个Notch1靶基因的表达，这表明在体内具有构成功能的重要性。这些数据表明，Piezo1是一种赋予ADAM10和Notch1力量敏感性的机制，并对Notch1靶基因的持续激活和潜在的其他过程产生下游影响。
Mechanical force is a determinant of Notch signalling but the mechanism of force detection and its coupling to Notch are unclear. We propose a role for Piezo1 channels, which are mechanically-activated non-selective cation channels. In cultured microvascular endothelial cells, Piezo1 channel activation by either shear stress or a chemical agonist Yoda1 activated a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), a Ca2+-regulated transmembrane sheddase that mediates S2 Notch1 cleavage. Consistent with this observation, we found Piezo1-dependent increase in the abundance of Notch1 intracellular domain (NICD) that depended on ADAM10 and the downstream S3 cleavage enzyme, gamma-secretase. Conditional endothelial-specific disruption of Piezo1 in adult mice suppressed the expression of multiple Notch1 target genes in hepatic vasculature, suggesting constitutive functional importance in vivo. The data suggest that Piezo1 is a mechanism conferring force sensitivity on ADAM10 and Notch1 with downstream consequences for sustained activation of Notch1 target genes and potentially other processes.