The Roles of Claudin Superfamily Proteins in Paracellular Transport

The claudin superfamily consists of at least 18 homologous proteins in humans. These proteins are important structural and functional components of tight junctions in paracellular transport. Complexed with two other integral transmembrane proteins, occludin and junctional adhesion molecule, claudins are located in both epithelial and endothelial cells in all tight junction‐bearing tissues. Claudins interact directly with tight junction‐specific, membrane‐associated guanylate kinase homologues, ZO‐1, ZO‐2, and ZO‐3, and indirectly with AF‐6 and the myosin‐binding molecule cingulin. These protein–protein interactions promote scaffolding of the tight junction transmembrane proteins and provide a link to the actin cytoskeleton for transducing regulatory signals to and from tight junctions. The distinct permeability properties observed in different epithelia and endothelia seemingly result from the restricted tissue expression, variability of the homopolymer and heteropolymer assembly, regulated transcription and translation, and the subcellular localization of claudin family proteins. Defects in claudins are causatively associated with a variety of human diseases, demonstrating that claudins play important roles in human physiology. In conditions where the cell adhesion function contributed by tight junctions is essential, such as in altered paracellular transport, in proliferative diseases, and during morphogenesis, the claudin superfamily of homologous proteins provides the molecular basis for the uniqueness of tight junctions and emerges as a new target for intervention.