Tight junction channel regulation by interclaudin interference

Nitesh Shashikanth, Marion M. France, Ruyue Xiao, Xenia Haest, Heather E. Rizzo, Jose Yeste, Johannes Reiner and Jerrold R. Turner ()
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Nitesh Shashikanth: Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School
Marion M. France: Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School
Ruyue Xiao: Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School
Xenia Haest: Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School
Heather E. Rizzo: Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School
Jose Yeste: Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School
Johannes Reiner: Division of Gastroenterology and Endocrinology, Department of Medicine II, Rostock University Medical Center, Ernst-Heydemann-Str. 6
Jerrold R. Turner: Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract Tight junctions form selectively permeable seals across the paracellular space. Both barrier function and selective permeability have been attributed to members of the claudin protein family, which can be categorized as pore-forming or barrier-forming. Here, we show that claudin-4, a prototypic barrier-forming claudin, reduces paracellular permeability by a previously unrecognized mechanism. Claudin-4 knockout or overexpression has minimal effects on tight junction permeability in the absence of pore-forming claudins. However, claudin-4 selectively inhibits flux across cation channels formed by claudins 2 or 15. Claudin-4-induced loss of claudin channel function is accompanied by reduced anchoring and subsequent endocytosis of pore-forming claudins. Analyses in nonepithelial cells show that claudin-4, which is incapable of independent polymerization, disrupts polymeric strands and higher order meshworks formed by claudins 2, 7, 15, and 19. This process of interclaudin interference, in which one claudin disrupts higher order structures and channels formed by a different claudin, represents a previously unrecognized mechanism of barrier regulation.

Date: 2022
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DOI: 10.1038/s41467-022-31587-8

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