Journal Article

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

Dorsainvil White, StevenClaude, Molina, Samuel A., Lynn, K. Sabrina, Mitchell, Leslie A., Schlingmann, Barbara, Guidot, David M., Overgaard, Christian E., Mattheyses, Alexa L., Koval, Michael, Capaldo, Christopher T.

2016

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 14 / 14/19 / 14/34 / 14/35 / 631/378/1689/5 / 631/80/79/1987 / 631/80/86 / 692/699/1785 / 82 / 82/1 / 82/80 / Action Potentials - drug effects / Alcoholism / Alcohols - toxicity / Animals / Claudin-5 - chemistry / Claudin-5 - metabolism / Cytoplasmic Vesicles - metabolism / Epithelial Cells - drug effects / Epithelial Cells - metabolism / Humanities and Social Sciences / Male / Membrane Fusion / multidisciplinary / Peptides / Peptides - metabolism / Permeability / Protein Binding - drug effects / Protein Domains / Proteins / Pulmonary Alveoli - pathology / Rats, Sprague-Dawley / Respiratory distress syndrome / Science / Science (multidisciplinary) / Solubility / Tight Junctions - metabolism / Up-Regulation - drug effects / Zonula Occludens-1 Protein - metabolism