Cell Adhesion at the Tight Junctions: New Aspects and New Functions

Abstract

Tight junctions (TJ) are cell-cell adhesive structures that define the permeability of barrier-forming epithelia and endothelia. In contrast to this seemingly static function, TJs display a surprisingly high molecular complexity and unexpected dynamic regulation, which allows the TJs to maintain a barrier in the presence of physiological forces and in response to perturbations. Cell-cell adhesion receptors play key roles during the dynamic regulation of TJs. They connect individual cells within cellular sheets and link sites of cell-cell contacts to the underlying actin cytoskeleton. Recent findings support the roles of adhesion receptors in transmitting mechanical forces and promoting phase separation. In this review, we discuss the newly discovered functions of cell adhesion receptors localized at the TJs and their role in the regulation of the barrier function.

Keywords: JAM-A; cell–cell adhesion; force sensing; junctional adhesion molecule; phase separation; tight junction.

Figure 1

Integral membrane proteins at TJs and their interaction with scaffolding proteins. Tight junctions contain a number of membrane proteins including Crumbs3 (CRB3), claudins, TJ-associated marvel proteins (Occludin, MarvelD3, Tricellulin), and members of the immunoglobulin superfamily (JAMs, CAR, ESAM, Angulins). All membrane proteins at the TJ directly interact with one or several scaffolding proteins (depicted in grey color). Some scaffolding proteins interact with several integral membrane proteins, as well as with other scaffolding proteins. For example, MUPP1 can interact with JAM-A, CAR, and claudins, as well as with PALS-1, PAR-6, and ZO-3 (indicated by arrows). Tricellulin and angulins are specifically localized at tricellular TJs.

Figure 2

Membrane proteins at tricellular TJs and their association with cytoplasmic proteins. (A) Tricellulin is linked to the actomyosin network via α-catenin (α-Cat) and vinculin (Vinc). MyosinII-driven contraction of antiparallel actin filaments (indicated by broken line and force vector symbols) associated with tricellulin generates a close apposition of the central sealing elements originating from the three cells to minimize the intercellular space at tTJs. (B) Besides its role in recruiting tricellulin, angulin-1 also recruits ZO-1 and claudin-2 to the central sealing elements of the TJs, which are formed by vertical TJ strands (see text for details).

Figure 3

TJ regulation via mechanical forces. Soft substrates impose only weak forces on TJs, allowing ZO-1 and ZO-2 to adopt a closed conformation that does not interact with occludin. When grown on stiff substrates, the actomyosin-driven contractility of the actin cytoskeleton imposes mechanical forces on ZO-1, which adopts an open conformation. Open ZO-1 can recruit occludin and transcription factors like DbpA to regulate barrier function and gene expression. JAM-A controls actomyosin-based contractility at TJs by preventing the recruitment of p114RhoGEF to TJs through an unknown mechanism, thus limiting the mechanical load on TJs.