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A weak link with actin organizes tight junctions to control epithelial permeability

Brian Belardi, Tiama Hamkins-Indik, Andrew R. Harris, View ORCID ProfileDaniel A. Fletcher
doi: https://doi.org/10.1101/805689
Brian Belardi
1Department of Bioengineering and Biophysics Program, University of California, Berkeley, CA, 94720 USA
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Tiama Hamkins-Indik
1Department of Bioengineering and Biophysics Program, University of California, Berkeley, CA, 94720 USA
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Andrew R. Harris
1Department of Bioengineering and Biophysics Program, University of California, Berkeley, CA, 94720 USA
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Daniel A. Fletcher
1Department of Bioengineering and Biophysics Program, University of California, Berkeley, CA, 94720 USA
2Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720 USA
3Chan Zuckerberg Biohub, San Francisco, CA 94158
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  • ORCID record for Daniel A. Fletcher
  • For correspondence: fletch@berkeley.edu
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SUMMARY

In vertebrates, epithelial permeability is regulated by the tight junction (TJ) formed by specialized adhesive membrane proteins, adaptor proteins, and the actin cytoskeleton. Despite the TJ’s critical physiological role, a molecular-level understanding of how TJ assembly sets the permeability of epithelial tissue is lacking. Here, we identify a 28-amino acid sequence in the TJ adaptor protein ZO-1 that is responsible for actin binding and show that this interaction is essential for TJ permeability. In contrast to the strong interactions at the adherens junction, we find that the affinity between ZO-1 and actin is surprisingly weak, and we propose a model based on kinetic trapping to explain how affinity could affect TJ assembly. Finally, by tuning the affinity of ZO-1 to actin, we demonstrate that epithelial monolayers can be engineered with a spectrum of permeabilities, which points to a new target for treating transport disorders and improving drug delivery.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 16, 2019.
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A weak link with actin organizes tight junctions to control epithelial permeability
Brian Belardi, Tiama Hamkins-Indik, Andrew R. Harris, Daniel A. Fletcher
bioRxiv 805689; doi: https://doi.org/10.1101/805689
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A weak link with actin organizes tight junctions to control epithelial permeability
Brian Belardi, Tiama Hamkins-Indik, Andrew R. Harris, Daniel A. Fletcher
bioRxiv 805689; doi: https://doi.org/10.1101/805689

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