Inter-Cellular Exchange of Cellular Components via VE-Cadherin-Dependent Trans-Endocytosis

Cell-cell communications typically involve receptor-mediated signaling initiated by soluble or cell-bound ligands. Here, we report a unique mode of endocytosis: proteins originating from cell-cell junctions and cytosolic cellular components from the neighboring cell are internalized, leading to direct exchange of cellular components between two adjacent endothelial cells. VE-cadherins form transcellular bridges between two endothelial cells that are the basis of adherence junctions. At such adherens junction sites, we observed the movement of the entire VE-cadherin molecule from one endothelial cell into the other with junctional and cytoplasmic components. This phenomenon, here termed trans-endocytosis, requires the establishment of a VE-cadherin homodimer in trans with internalization proceeding in a Rac1-, and actomyosin-dependent manner. Importantly, the trans-endocytosis is not dependent on any known endocytic pathway including clathrin-dependent endocytosis, macropinocytosis or phagocytosis. This novel form of cell-cell communications, leading to a direct exchange of cellular components, was observed in 2D and 3D-cultured endothelial cells as well as in the developing zebrafish vasculature.

细胞间通讯通常涉及由可溶性配体或细胞结合型配体启动的受体介导信号转导。
本研究报道了一种独特的内吞作用模式：源自细胞间连接的蛋白质以及邻近细胞的胞质组分被内化，进而实现两个相邻内皮细胞间的细胞组分直接交换。
VE-钙粘蛋白（VE-cadherin）可在两个内皮细胞之间形成跨细胞桥，这是细胞粘附连接的结构基础。
在这类粘附连接位点，我们观察到完整的VE-钙粘蛋白分子连同连接组分与胞质成分，从一个内皮细胞转移至另一个内皮细胞。
这种被本文命名为跨细胞内吞作用（trans-endocytosis）的现象，需要以反式构型形成VE-钙粘蛋白同源二聚体，且内吞过程依赖于Rac1及肌动蛋白-肌球蛋白复合物。
值得注意的是，该跨细胞内吞作用不依赖于任何已知的内吞途径，包括网格蛋白依赖型内吞作用、巨胞饮作用以及吞噬作用。
这种可实现细胞组分直接交换的新型细胞间通讯模式，已在二维及三维培养的内皮细胞，以及发育中的斑马鱼血管系统中被观测到。