Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan.
Department of Morphological Biology, Fukuoka Dental College, Fukuoka, Japan.
J Cell Biol. 2018 Jul 2;217(7):2373-2381. doi: 10.1083/jcb.201711042. Epub 2018 May 2.
Tight junctions (TJs) are essential cell adhesion structures that act as a barrier to separate the internal milieu from the external environment in multicellular organisms. Although their major constituents have been identified, it is unknown how the formation of TJs is regulated. TJ formation depends on the preceding formation of adherens junctions (AJs) in epithelial cells; however, the underlying mechanism remains to be elucidated. In this study, loss of AJs in α-catenin-knockout (KO) EpH4 epithelial cells altered the lipid composition of the plasma membrane (PM) and led to endocytosis of claudins, a major component of TJs. Sphingomyelin with long-chain fatty acids and cholesterol were enriched in the TJ-containing PM fraction. Depletion of cholesterol abolished the formation of TJs. Conversely, addition of cholesterol restored TJ formation in α-catenin-KO cells. Collectively, we propose that AJs mediate the formation of TJs by increasing the level of cholesterol in the PM.
紧密连接（TJs）是多细胞生物中重要的细胞粘附结构，作为将内部环境与外部环境分隔开的屏障。尽管已经确定了它们的主要成分，但 TJs 的形成如何受到调节仍不清楚。TJ 的形成依赖于上皮细胞中粘着连接（AJs）的先前形成；然而，其潜在机制仍有待阐明。在这项研究中，α-连环蛋白敲除（KO）EpH4 上皮细胞中 AJ 的缺失改变了质膜（PM）的脂质组成，并导致 TJ 的主要成分紧密连接蛋白的内吞作用。长链脂肪酸和胆固醇的神经鞘磷脂在含有 TJ 的 PM 部分中富集。胆固醇耗竭会破坏 TJ 的形成。相反，胆固醇的添加可恢复 α-连环蛋白 KO 细胞中的 TJ 形成。总之，我们提出 AJ 通过增加 PM 中的胆固醇水平来介导 TJ 的形成。
