Claudin-23 reshapes epithelial tight junction architecture to regulate barrier function

• Type of Material: Article
• Authors: Arturo Raya-Sandino, University of Michigan, Ann Arbor; Kristen M. Locado-Soto, University of Michigan, Ann Arbor; Nandhini Rajagopal, Syracuse University; Vicky Garcia-Hernandez, University of Michigan, Ann Arbor; Anny-Claude Luissint, University of Michigan, Ann Arbor; Jennifer C. Brazil, University of Michigan, Ann Arbor; Guiying Cui, Emory University; Michael Koval, Emory University; Charles A. Parkos, University of Michigan, Ann Arbor; Shikha Nangi, Syracuse University; Asma Musrat, University of Michigan, Ann Arbor
• Language: English
• Date: 2023-10-05
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2023
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1038/s41467-023-41999-9
• Title of Journal or Parent Work: Nature Communications
• Volume: 14
• Start Page: 6214
• Grant/Funding Information: This work was supported by the following grants: Crohn’s and Colitis Foundation Research Fellowship no. 623536 (A.R.-S.), Training in Basic and Translational Digestive Sciences T32 DK094775 (K.M.L.-S.), National Science Foundation CAREER CBET-1453312 (S.N.), National Institutes of Health F30 DK132817 (K.M.L.-S.), R01 AA025854 and R01 HL158979 (M.K.), R01 DK61739 and DK72564 (C.A.P.), and R01 DK059888 and DK055679 (A.N.), RO1 129214 (A.N. and C.A.P.) and University of Michigan Center for Gastrointestinal Research (UMCGR), (NIDDK 5P30DK034933).
• Keywords: Gastrointestinal system; Molecular modelling; Tight junctions
• Research Categories: Biology, Cell; Biology, Molecular

Abstract

Claudin family tight junction proteins form charge- and size-selective paracellular channels that regulate epithelial barrier function. In the gastrointestinal tract, barrier heterogeneity is attributed to differential claudin expression. Here, we show that claudin-23 (CLDN23) is enriched in luminal intestinal epithelial cells where it strengthens the epithelial barrier. Complementary approaches reveal that CLDN23 regulates paracellular ion and macromolecule permeability by associating with CLDN3 and CLDN4 and regulating their distribution in tight junctions. Computational modeling suggests that CLDN23 forms heteromeric and heterotypic complexes with CLDN3 and CLDN4 that have unique pore architecture and overall net charge. These computational simulation analyses further suggest that pore properties are interaction-dependent, since differently organized complexes with the same claudin stoichiometry form pores with unique architecture. Our findings provide insight into tight junction organization and propose a model whereby different claudins combine to form multiple distinct complexes that modify epithelial barrier function by altering tight junction structure.