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

Barbara Schlingmann, Christian E. Overgaard, Samuel A. Molina, K. Sabrina Lynn, Leslie A. Mitchell, StevenClaude Dorsainvil White, Alexa L. Mattheyses, David M. Guidot, Christopher T. Capaldo and Michael Koval ()
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Barbara Schlingmann: Allergy, Critical Care and Sleep Medicine, Emory University
Christian E. Overgaard: Allergy, Critical Care and Sleep Medicine, Emory University
Samuel A. Molina: Allergy, Critical Care and Sleep Medicine, Emory University
K. Sabrina Lynn: Allergy, Critical Care and Sleep Medicine, Emory University
Leslie A. Mitchell: Allergy, Critical Care and Sleep Medicine, Emory University
StevenClaude Dorsainvil White: Allergy, Critical Care and Sleep Medicine, Emory University
Alexa L. Mattheyses: Emory University
David M. Guidot: Allergy, Critical Care and Sleep Medicine, Emory University
Christopher T. Capaldo: Department of Pathology
Michael Koval: Allergy, Critical Care and Sleep Medicine, Emory University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms12276

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