Nanoscale segregation of channel and barrier claudins enables paracellular ion flux

Hannes Gonschior, Christopher Schmied, Rozemarijn Eva Van der Veen, Jenny Eichhorst, Nina Himmerkus, Jörg Piontek, Dorothee Günzel, Markus Bleich, Mikio Furuse, Volker Haucke and Martin Lehmann ()
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Hannes Gonschior: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Christopher Schmied: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Rozemarijn Eva Van der Veen: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Jenny Eichhorst: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Nina Himmerkus: Institute of Physiology, Christian-Albrechts-Universität zu Kiel
Jörg Piontek: Charité – Universitätsmedizin Berlin
Dorothee Günzel: Charité – Universitätsmedizin Berlin
Markus Bleich: Institute of Physiology, Christian-Albrechts-Universität zu Kiel
Mikio Furuse: National Institute for Physiological Sciences
Volker Haucke: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Martin Lehmann: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract The paracellular passage of ions and small molecules across epithelia is controlled by tight junctions, complex meshworks of claudin polymers that form tight seals between neighboring cells. How the nanoscale architecture of tight junction meshworks enables paracellular passage of specific ions or small molecules without compromising barrier function is unknown. Here we combine super-resolution stimulated emission depletion microscopy in live and fixed cells and tissues, multivariate classification of super-resolution images and fluorescence resonance energy transfer to reveal the nanoscale organization of tight junctions formed by mammalian claudins. We show that only a subset of claudins can assemble into characteristic homotypic meshworks, whereas tight junctions formed by multiple claudins display nanoscale organization principles of intermixing, integration, induction, segregation, and exclusion of strand assemblies. Interestingly, channel-forming claudins are spatially segregated from barrier-forming claudins via determinants mainly encoded in their extracellular domains also known to harbor mutations leading to human diseases. Electrophysiological analysis of claudins in epithelial cells suggests that nanoscale segregation of distinct channel-forming claudins enables barrier function combined with specific paracellular ion flux across tight junctions.

Date: 2022
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DOI: 10.1038/s41467-022-32533-4

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