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

Arturo Raya-Sandino, Kristen M. Lozada-Soto, Nandhini Rajagopal, Vicky Garcia-Hernandez, Anny-Claude Luissint, Jennifer C. Brazil, Guiying Cui, Michael Koval, Charles A. Parkos, Shikha Nangia () and Asma Nusrat ()
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Arturo Raya-Sandino: University of Michigan Medical School
Kristen M. Lozada-Soto: University of Michigan Medical School
Nandhini Rajagopal: Syracuse University
Vicky Garcia-Hernandez: University of Michigan Medical School
Anny-Claude Luissint: University of Michigan Medical School
Jennifer C. Brazil: University of Michigan Medical School
Guiying Cui: Emory University School of Medicine
Michael Koval: Emory University School of Medicine
Charles A. Parkos: University of Michigan Medical School
Shikha Nangia: Syracuse University
Asma Nusrat: University of Michigan Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-22

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41999-9

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