Nanoscale segregation of channel and barrier claudins enables paracellular ion flux.
Nanoscale segregation of channel and barrier claudins enables paracellular ion flux.
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DOI：
10.1038/s41467-022-32533-4
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发表时间：
2022-08-25
影响因子：
16.6
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中科院分区：
文献类型：
--
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离子和小分子穿过上皮的细胞旁通道由紧密连接控制，紧密连接是紧密连接蛋白聚合物的复杂网络，其在相邻细胞之间形成紧密密封。紧密连接网络的纳米级结构如何使特定离子或小分子能够在不损害屏障功能的情况下通过细胞旁通道尚不清楚。在这里，我们结合联合收割机的超分辨率受激发射损耗显微镜在活的和固定的细胞和组织，多变量分类的超分辨率图像和荧光共振能量转移，以揭示纳米级组织的紧密连接形成的哺乳动物claudins。我们发现，只有一个子集的claudins可以组装成特征的同型网状结构，而紧密连接形成的多个claudins显示纳米级的组织原则的混合，整合，诱导，隔离和排除链组件。有趣的是，形成通道的密蛋白通过主要在其细胞外结构域中编码的决定簇与形成屏障的密蛋白在空间上分离，所述细胞外结构域也已知含有导致人类疾病的突变。上皮细胞中的密蛋白的电生理学分析表明，不同的通道形成密蛋白的纳米级隔离，使屏障功能结合特定的细胞旁离子通量通过紧密连接。密蛋白聚合物的网状结构控制上皮紧密连接的细胞旁转运和屏障性质。在这里，作者展示了不同的claudin纳米级组织原理，发现claudin分离使屏障形成和细胞旁离子通量穿过紧密连接。
The paracellular passage of ions and small molecules across epithelia is controlled by tight junctions, complex meshworks of claudin polymers that form tight seals between neighboring cells. How the nanoscale architecture of tight junction meshworks enables paracellular passage of specific ions or small molecules without compromising barrier function is unknown. Here we combine super-resolution stimulated emission depletion microscopy in live and fixed cells and tissues, multivariate classification of super-resolution images and fluorescence resonance energy transfer to reveal the nanoscale organization of tight junctions formed by mammalian claudins. We show that only a subset of claudins can assemble into characteristic homotypic meshworks, whereas tight junctions formed by multiple claudins display nanoscale organization principles of intermixing, integration, induction, segregation, and exclusion of strand assemblies. Interestingly, channel-forming claudins are spatially segregated from barrier-forming claudins via determinants mainly encoded in their extracellular domains also known to harbor mutations leading to human diseases. Electrophysiological analysis of claudins in epithelial cells suggests that nanoscale segregation of distinct channel-forming claudins enables barrier function combined with specific paracellular ion flux across tight junctions. Meshworks of claudin polymers control the paracellular transport and barrier properties of epithelial tight junctions. Here, the authors show different claudin nanoscale organization principles, finding that claudin segregation enables barrier formation and paracellular ion flux across tight junctions.
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影响因子：
7.8
作者：
Furuse, Mikio;Hata, Masaki;Furuse, Kyoko;Yoshida, Yoko;Haratake, Akinori;Sugitani, Yoshinobu;Noda, Tetsuo;Kubo, Akiharu;Tsukita, Shoichiro
通讯作者：
Tsukita, Shoichiro
影响因子：
3.4
作者：
Hall-Beyer, Mryka
通讯作者：
Hall-Beyer, Mryka
影响因子：
2.4
作者：
CLAUDE, P
通讯作者：
CLAUDE, P
影响因子：
5.6
作者：
Hempel, C.;Protze, J.;Piontek, J.
通讯作者：
Piontek, J.
影响因子：
13.6
作者：
Breiderhoff, Tilman;Himmerkus, Nina;Guenzel, Dorothee
通讯作者：
Guenzel, Dorothee