Regulation of claudin/zonula occludens-1 complexes by hetero-claudin interactions.
Regulation of claudin/zonula occludens-1 complexes by hetero-claudin interactions.
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DOI：
10.1038/ncomms12276
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发表时间：
2016-07-25
影响因子：
16.6
通讯作者：
Koval M
中科院分区：
文献类型：
--
作者：
Schlingmann B;Overgaard CE;Molina SA;Lynn KS;Mitchell LA;Dorsainvil White S;Mattheyses AL;Guidot DM;Capaldo CT;Koval M
Claudins是一种调节上皮屏障的四环素跨膜紧密连接蛋白。在肺的远端空隙中，肺泡上皮紧密连接是调节空隙液体的关键。长期酗酒会削弱肺泡紧密连接，使肺部患上急性呼吸窘迫综合征，这是一种经常由空域泛滥引起的致命疾病。在这里，我们证明，在酒精的反应下，claudin-5的增加矛盾地伴随着细胞旁泄漏的增加和肺泡紧密连接的重排。Claudin-5是必要且充分的，通过损害Claudin-18与支架蛋白ZO-1(ZO-1)相互作用的能力来削弱肺泡上皮屏障功能，表明一种Claudin影响另一种Claudin与紧密连接支架相互作用的能力。关键的是，claudin-5肽的模拟物可以逆转酒精对肺泡屏障功能的有害影响。因此，claudin控制的claudin-支架蛋白相互作用是调节紧密连接通透性的新靶点。酗酒是急性呼吸窘迫综合征的危险因素，急性呼吸窘迫综合征是由于屏障功能受损而导致的肺水泛滥。在这里，作者报告说，酒精上调claudin-5，然后被招募到肺泡上皮细胞的紧密连接，导致claudin-18从ZO-1置换，并降低屏障功能。
Claudins are tetraspan transmembrane tight-junction proteins that regulate epithelial barriers. In the distal airspaces of the lung, alveolar epithelial tight junctions are crucial to regulate airspace fluid. Chronic alcohol abuse weakens alveolar tight junctions, priming the lung for acute respiratory distress syndrome, a frequently lethal condition caused by airspace flooding. Here we demonstrate that in response to alcohol, increased claudin-5 paradoxically accompanies an increase in paracellular leak and rearrangement of alveolar tight junctions. Claudin-5 is necessary and sufficient to diminish alveolar epithelial barrier function by impairing the ability of claudin-18 to interact with a scaffold protein, zonula occludens 1 (ZO-1), demonstrating that one claudin affects the ability of another claudin to interact with the tight-junction scaffold. Critically, a claudin-5 peptide mimetic reverses the deleterious effects of alcohol on alveolar barrier function. Thus, claudin controlled claudin-scaffold protein interactions are a novel target to regulate tight-junction permeability. Alcohol abuse is a risk factor for acute respiratory distress syndrome, flooding of the lungs due to compromised barrier function. Here the authors report that alcohol upregulates claudin-5 that is then recruited to tight junctions in alveolar epithelial cells, causing the displacement of claudin-18 from ZO-1 and diminished barrier function.