Claudins and JAM-A coordinately regulate tight junction formation and epithelial polarity
Claudins and JAM-A coordinately regulate tight junction formation and epithelial polarity
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DOI：
10.1083/jcb.201812157
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发表时间：
2019-10-01
影响因子：
7.8
通讯作者：
Furuse, Mikio
中科院分区：
文献类型：
--
作者：
Otani, Tetsuhisa;Thanh Phuong Nguyen;Furuse, Mikio
紧密连接（TJs）建立上皮屏障，并被认为是形成膜栅栏来调节上皮极性，尽管TJs在上皮极性中的作用仍然存在争议。紧密连接蛋白与细胞质支架ZO-1和ZO-2一起构成TJ链，并在上皮屏障形成中发挥关键作用。然而，封闭蛋白和其他TJ膜蛋白如何合作组织TJ仍不清楚。在这里，我们通过基因组编辑系统地敲除了TJ组分，并表明ZO-1/ZO-2缺陷细胞缺乏TJ结构和上皮屏障，而claudin缺陷细胞缺乏TJ链和电解质渗透屏障，但形成了膜并置和大分子渗透屏障。此外，上皮极性紊乱ZO-1/ZO-2缺陷细胞，但不是在claudin缺陷细胞。同时删除封闭蛋白和TJ膜蛋白JAM-A导致膜沉积和大分子渗透屏障的损失和零星的上皮极性缺陷。这些结果表明，密封蛋白和JAM-A协调调节TJ形成和上皮极性。
Tight junctions (TJs) establish the epithelial barrier and are thought to form a membrane fence to regulate epithelial polarity, although the roles of TJs in epithelial polarity remain controversial. Claudins constitute TJ strands in conjunction with the cytoplasmic scaffolds ZO-1 and ZO-2 and play pivotal roles in epithelial barrier formation. However, how claudins and other TJ membrane proteins cooperate to organize TJs remains unclear. Here, we systematically knocked out TJ components by genome editing and show that while ZO-1/ZO-2-deficient cells lacked TJ structures and epithelial barriers, claudin-deficient cells lacked TJ strands and an electrolyte permeability barrier but formed membrane appositions and a macromolecule permeability barrier. Moreover, epithelial polarity was disorganized in ZO-1/ZO-2-deficient cells, but not in claudin-deficient cells. Simultaneous deletion of claudins and a TJ membrane protein JAM-A resulted in a loss of membrane appositions and a macromolecule permeability barrier and in sporadic epithelial polarity defects. These results demonstrate that claudins and JAM-A coordinately regulate TJ formation and epithelial polarity.