Tight Junction Structure and Function Revisited

Tight junctions (TJs) are intercellular junctions critical for building the epithelial barrier and maintaining epithelial polarity. The claudin family of membrane proteins play central roles in TJ structure and function. However, recent findings have uncovered claudin-independent aspects of TJ structure and function, and additional players including junctional adhesion molecules (JAMs), membrane lipids, phase separation of the zonula occludens (ZO) family of scaffolding proteins, and mechanical force have been shown to play important roles in TJ structure and function. In this review, we discuss how these new findings have the potential to transform our understanding of TJ structure and function, and how the intricate network of TJ proteins and membrane lipids dynamically interact to drive TJ assembly. Tight junction strand formation and membrane apposition formation are differentially regulated.Claudins form charge-selective small pores, while junctional adhesion molecules regulate the formation of size-selective large pores.Tight junction proteins regulate epithelial polarity, although how tight junctions form a membrane fence remains unclear.Tight junction associated membrane proteins regulate tight junction assembly in conjunction with zonula occludens protein phase separation, membrane lipids, mechanical force, and polarity signaling proteins.