Raya-Sandino Arturo, Lozada-Soto Kristen M, Rajagopal Nandhini, Garcia-Hernandez Vicky, Luissint Anny-Claude, Brazil Jennifer C, Cui Guiying, Koval Michael, Parkos Charles A, Nangia Shikha, Nusrat Asma
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
Department of Biomedical and Chemical Engineering, Syracuse University, Syracuse, NY, USA.
Nat Commun. 2023 Oct 5;14(1):6214. doi: 10.1038/s41467-023-41999-9.
Claudin family tight junction proteins form charge- and size-selective paracellular channels that regulate epithelial barrier function. In the gastrointestinal tract, barrier heterogeneity is attributed to differential claudin expression. Here, we show that claudin-23 (CLDN23) is enriched in luminal intestinal epithelial cells where it strengthens the epithelial barrier. Complementary approaches reveal that CLDN23 regulates paracellular ion and macromolecule permeability by associating with CLDN3 and CLDN4 and regulating their distribution in tight junctions. Computational modeling suggests that CLDN23 forms heteromeric and heterotypic complexes with CLDN3 and CLDN4 that have unique pore architecture and overall net charge. These computational simulation analyses further suggest that pore properties are interaction-dependent, since differently organized complexes with the same claudin stoichiometry form pores with unique architecture. Our findings provide insight into tight junction organization and propose a model whereby different claudins combine to form multiple distinct complexes that modify epithelial barrier function by altering tight junction structure.
闭合蛋白家族紧密连接蛋白形成具有电荷和大小选择性的细胞旁通道，调节上皮屏障功能。在胃肠道中，屏障异质性归因于闭合蛋白的差异表达。在此，我们表明闭合蛋白-23（CLDN23）在肠腔上皮细胞中富集，它在其中增强上皮屏障。互补方法表明，CLDN23通过与CLDN3和CLDN4结合并调节它们在紧密连接中的分布来调节细胞旁离子和大分子通透性。计算模型表明，CLDN23与CLDN3和CLDN4形成具有独特孔结构和整体净电荷的异源和异型复合物。这些计算模拟分析进一步表明，孔特性是相互作用依赖的，因为具有相同闭合蛋白化学计量的不同组织的复合物形成具有独特结构的孔。我们的研究结果为紧密连接组织提供了见解，并提出了一个模型，即不同的闭合蛋白结合形成多个不同的复合物，通过改变紧密连接结构来改变上皮屏障功能。
