Review Article

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

Authors: Shuang Sun1, Jun Zhou2
1 Institute of Biomedical Sciences, Shandong Provincial Key Laboratory of Animal Resistance Biology, Collaborative Innovation Center of Cell Biology in Universities of Shandong, College of Life Sciences, Shandong Normal University, Jinan 250014, China
2 State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China
Correspondence to: Shuang Sun:, Jun Zhou:,
DOI: 10.1038/s41401-020-0470-y
Received: 28 April 2020
Accepted: 28 June 2020
Advance online: 21 July 2020


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.
Keywords: tight junction; Zonula occludens; protein–protein interaction; phase separation; paracellular permeability; tumor invasion and metastasis; hypertension; cystic fibrosis; hypomagnesaemia

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