Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Department of Biological Science, Graduate School of Science, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8526, Japan.
Development. 2019 Feb 15;146(4):dev169037. doi: 10.1242/dev.169037.
Non-apoptotic caspase activation involves multiple cellular events. However, the link between visible non-apoptotic caspase activation and its function in living organisms has not yet been revealed. Here, we visualized sub-lethal activation of apoptotic signaling with the combination of a sensitive indicator for caspase 3 activation and live-imaging analysis of During thorax closure in pupal development, caspase 3 activation was specifically observed at the leading edge cells, with no signs of apoptosis. Inhibition of caspase activation led to an increase in thorax closing speed, which suggests a role of non-apoptotic caspase activity in cell motility. Importantly, sub-lethal activation of caspase 3 was also observed during wound closure at the fusion sites at which thorax closure had previously taken place. Further genetic analysis revealed that the activation of the initiator caspase Dronc is coupled with the generation of reactive oxygen species. The activation of Dronc also regulates myosin levels and delays wound healing. Our findings suggest a possible function for non-apoptotic caspase activation in the fine-tuning of cell migratory behavior during epithelial closure.
非凋亡性半胱天冬酶的激活涉及多种细胞事件。然而，可见的非凋亡性半胱天冬酶的激活与其在生物体中的功能之间的联系尚未被揭示。在这里，我们通过将 caspase 3 激活的敏感指示剂与活体成像分析相结合，可视化亚致死性凋亡信号的激活。在蛹发育过程中的胸节关闭过程中，caspase 3 的激活仅在前沿细胞中观察到，没有凋亡的迹象。抑制半胱天冬酶的激活导致胸节关闭速度的增加，这表明非凋亡性半胱天冬酶活性在细胞运动中起作用。重要的是，在先前发生胸节关闭的融合部位的伤口闭合过程中也观察到 caspase 3 的亚致死性激活。进一步的遗传分析表明，起始半胱天冬酶 Dronc 的激活与活性氧的产生有关。Dronc 的激活还调节肌球蛋白水平并延迟伤口愈合。我们的研究结果表明，非凋亡性半胱天冬酶的激活可能在上皮细胞闭合过程中精细调节细胞迁移行为方面发挥作用。
