PDF(Pubmed)
Abstract：
Zonula occludens-1 (ZO-1) is involved in the regulation of cell-cell junctions between endothelial cells (ECs). Here we identify the ZO-1 protein interactome and uncover ZO-1 interactions with RNA-binding proteins that are part of stress granules (SGs). Downregulation of ZO-1 increased SG formation in response to stress and protected ECs from cellular insults. The ZO-1 interactome uncovered an association between ZO-1 and Y-box binding protein 1 (YB-1), a constituent of SGs. Arsenite treatment of ECs decreased the interaction between ZO-1 and YB-1, and drove SG assembly. YB-1 expression is essential for SG formation and for the cytoprotective effects induced by ZO-1 downregulation. In the developing retinal vascular plexus of newborn mice, ECs at the front of growing vessels express less ZO-1 but display more YB-1-positive granules than ECs located in the vascular plexus. Endothelial-specific deletion of ZO-1 in mice at post-natal day 7 markedly increased the presence of YB-1-positive granules in ECs of retinal blood vessels, altered tip EC morphology and vascular patterning, resulting in aberrant endothelial proliferation, and arrest in the expansion of the retinal vasculature. Our findings suggest that, through its interaction with YB-1, ZO-1 controls SG formation and the response of ECs to stress during angiogenesis.
摘要：
Zonula闭塞-1（ZO-1）参与内皮细胞（EC）之间的细胞-细胞连接的调节。在这里，我们确定了ZO-1蛋白相互作用组，并揭示了ZO-1与作为应激颗粒（SGs）一部分的RNA结合蛋白的相互作用。ZO-1的下调增加了对压力的反应的SG形成，并保护了EC免受细胞损伤。ZO-1相互作用组揭示了ZO-1和Y盒结合蛋白1（YB-1）之间的关联，SGs的组成部分。亚砷酸盐处理ECs降低了ZO-1和YB-1之间的相互作用，并驱动了SG组装。YB-1表达对于SG形成和ZO-1下调诱导的细胞保护作用至关重要。在新生小鼠视网膜血管丛的发育中，与位于血管丛中的EC相比，生长血管前部的EC表达较少的ZO-1，但表现出更多的YB-1阳性颗粒。出生后第7天小鼠中ZO-1的内皮特异性缺失显着增加了视网膜血管ECs中YB-1阳性颗粒的存在，改变尖端EC形态和血管模式，导致异常的内皮增殖，并阻止视网膜血管的扩张。我们的研究结果表明,通过与YB-1的相互作用，ZO-1控制SG的形成和ECs对血管生成过程中应激反应。
