Podosome formation impairs endothelial barrier function by sequestering zonula occludens proteins.
Podosome formation impairs endothelial barrier function by sequestering zonula occludens proteins.
复制标题
足体形成通过隔离闭锁带蛋白损害内皮屏障功能。
DOI：
10.1002/jcp.29343
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发表时间：
2020
影响因子：
5.6
通讯作者：
Xu,Zhen
中科院分区：
文献类型：
--
作者：
Rui,Yan-Ning;Chen,Yawen;Guo,Yichen;Bock,CarolineE;Hagan,JohnP;Kim,DongH;Xu,Zhen
粒体和紧密连接（TJ）是存在于内皮细胞中并定位于细胞表面的亚细胞区室。与TJ在维持脑血管完整性方面的良好特征化作用相反，内皮podosomes的具体功能仍然未知。有趣的是，我们在人脑内皮细胞中发现了podosomes和TJ之间的串扰。紧密连接支架蛋白ZO-1和ZO-2定位于对佛波醇-12-肉豆蔻酸酯-13-乙酸酯处理作出响应的足体。我们发现，这两个ZO蛋白是必不可少的podosome的形成和功能。而不是来自新的蛋白质合成，足体ZO-1和ZO-2是从外周质膜上发现的预先存在的池中重新定位的，与coronin（一种已知的足体蛋白质标记物）的物理相互作用增强。ZO蛋白在podosomes中的隔离减弱了紧密连接复合物的形成，导致内皮细胞通透性增加。这种作用可以通过podosome抑制剂PP 2进一步减弱。总而言之，我们的数据揭示了一种新的细胞功能的podosomes，特别是，他们的能力，负调节紧密连接和内皮屏障的完整性，这已经与各种脑血管疾病。
Podosomes and tight junctions (TJs) are subcellular compartments that both exist in endothelial cells and localize at cell surfaces. In contrast to the well‐characterized role of TJs in maintaining cerebrovascular integrity, the specific function of endothelial podosomes remains unknown. Intriguingly, we discovered cross‐talk between podosomes and TJs in human brain endothelial cells. Tight junction scaffold proteins ZO‐1 and ZO‐2 localize at podosomes in response to phorbol‐12‐myristate‐13‐acetate treatment. We found that both ZO proteins are essential for podosome formation and function. Rather than being derived from new protein synthesis, podosomal ZO‐1 and ZO‐2 are relocated from a pre‐existing pool found at the peripheral plasma membrane with enhanced physical interaction with cortactin, a known protein marker for podosomes. Sequestration of ZO proteins in podosomes weakens tight junction complex formation, leading to increased endothelial cell permeability. This effect can be further attenuated by podosome inhibitor PP2. Altogether, our data revealed a novel cellular function of podosomes, specifically, their ability to negatively regulate tight junction and endothelial barrier integrity, which have been linked to a variety of cerebrovascular diseases.