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Phase separation as a therapeutic target in tight junction-associated human diseases

Abstract

Tight junctions (TJs) play an important role in the maintenance of epithelial and endothelial barriers. Zonula occludens (ZO) proteins are scaffolding molecules essential for the formation of TJ complexes, and abnormalities in ZO proteins have been implicated in various TJ-associated human diseases such as tumor invasion and metastasis, and barrier dysfunction. Recent studies reveal that liquid–liquid phase separation of ZO proteins drives the polymerization of TJ proteins into a continuous belt, which then recruits various proteins to form the TJ complex to regulate selective paracellular permeability and signal transduction. Herein, we describe recent advances on how ZO phase separation contributes to TJ formation and discuss the potential of phase separation as a target for the treatment of TJ-associated diseases.

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Fig. 1: Model of ZO-1 phase separation driving TJ formation.
Fig. 2: Mechanisms and strategies of targeting ZO-1 phase separation.

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Acknowledgements

This work was supported by a grant from the Natural Science Foundation of Shandong Province (ZR2018BC002).

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Correspondence to Shuang Sun or Jun Zhou.

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Sun, S., Zhou, J. Phase separation as a therapeutic target in tight junction-associated human diseases. Acta Pharmacol Sin 41, 1310–1313 (2020). https://doi.org/10.1038/s41401-020-0470-y

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Keywords

  • tight junction
  • Zonula occludens
  • protein–protein interaction
  • phase separation
  • paracellular permeability
  • tumor invasion and metastasis
  • hypertension
  • cystic fibrosis
  • hypomagnesaemia

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