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Nat Commun. 2016 Jul 25;7:12276. doi: 10.1038/ncomms12276.

Regulation of claudin/zonula occludens-1 complexes by hetero-claudin interactions.

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Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University, 205 Whitehead Building, 615 Michael Street, Atlanta, Georgia 30322, USA.
Emory Alcohol and Lung Biology Center, Emory University, Atlanta, Georgia 30322, USA.
Department of Cell Biology, Emory University, Atlanta, Georgia 30322, USA.
Atlanta Veterans Affairs Medical Center, Decatur, Georgia 30033, USA.
Department of Pathology; Emory University School of Medicine, Atlanta, GA 30322, USA.


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.

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