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Tight junction channel regulation by interclaudin interference

Author

Listed:
  • 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
    Instituto de Microelectrónica de Barcelona, IMB-CNM (CSIC))

  • 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)

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.

Suggested Citation

  • Nitesh Shashikanth & Marion M. France & Ruyue Xiao & Xenia Haest & Heather E. Rizzo & Jose Yeste & Johannes Reiner & Jerrold R. Turner, 2022. "Tight junction channel regulation by interclaudin interference," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31587-8
    DOI: 10.1038/s41467-022-31587-8
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    Cited by:

    1. 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, 2023. "Claudin-23 reshapes epithelial tight junction architecture to regulate barrier function," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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