Breaking into the epithelial apical-junctional complex--news from pathogen hackers

Abstract

The epithelial apical-junctional complex is a key regulator of cellular functions. In addition, it is an important target for microbial pathogens that manipulate the cell to survive, proliferate and sometimes persist within a host. Out of a myriad of potential molecular targets, some bacterial and viral pathogens have selected a subset of protein targets at the apical-junctional complex of epithelial cells. Studying how microbes use these targets also teaches us about the inherent physiological properties of host molecules in the context of normal junctional structure and function. Thus, we have learned that three recently uncovered components of the apical-junctional complex of the Ig superfamily--junctional adhesion molecule, Nectin and the coxsackievirus and adenovirus receptor--are important regulators of junction structure and function and represent critical targets of microbial virulence gene products.

Figure 1

Bacteria and viruses interact with, and disrupt, apical junctions of polarized epithelia. From left to right, examples of different AJC targets of pathogens. Clostridia (yellow) and Vibrio cholerae (blue-green) secrete enzymes that cleave tight junction membrane proteins. Pathogenic E. coli (blue) deliver bacterial toxins to the host cell, and affect tight junction function by disrupting the peri-junctional actin cytoskeleton. Listeria monocytogenes (brown) exemplifies a bacterium that disrupts junctions to enter epithelial cells and uses AJC components as receptors. Helicobacter pylori (purple) adheres to gastric epithelial cells near apical junctions and injects the bacterial protein CagA into the host cell. CagA interacts with scaffolding components, growth factor receptors and transmembrane molecules of the AJC leading to defects in tight-junction barrier functions and changes in cell polarity. Various unrelated viruses (green) such as adenovirus, coxsackievirus, reovirus, and herpesvirus interact with transmembrane AJC components of the immunoglobulin superfamily. This is important for both viral entry into cells and exit from the basal-lateral surface to reach the apical surface.

Figure 2

The apical–junctional complex is organized into structural and regulatory domains by protein sub-complexes. Junctions are held together by transmembrane molecules of the occludin, claudin, cadherin and immunoglobulin superfamilies (red shading denotes proteins with a transmembrane role). Each transmembrane protein is linked via its cytoplasmic tail to scaffolding proteins of the ZO, afadin or catenin families (blue shading denotes proteins with a scaffolding role). Scaffolding proteins then form complexes with multiple signaling and adaptor proteins. For example, the Par3/Par6/aPKC/Rho-GTPase protein complex (purple shading), which is involved in regulating epithelial polarity, is linked to JAM. Scaffolding proteins also link transmembrane proteins to the peri-junctional actin cytoskeleton and its associated proteins and connect different sub-complexes with each other. The apical junctions are traditionally divided into tight and adherens junctions. The tight junctions form the epithelial barrier via their transmembrane proteins claudins and occludin. These are linked to the actin cytoskeleton through scaffolding proteins of the ZO family. At the adherens junction, E-cadherin is linked to the peri-junctional actin via β and α-catenins. These structural domains of the junctions (yellow shading) interact with regulatory protein sub-complexes that are involved in the control of cell polarity, cell division, cell movement and junction assembly. Several regulatory sub-complexes use transmembrane proteins of the immunoglobulin superfamily, such as JAM, CAR and nectin. Other regulatory systems include receptor tyrosine kinases such as c-met. (The key shows examples of the types of molecules at the AJC and is not meant to be exhaustive.)

Figure 3

Structural and regulatory sub-complexes of the AJC are targets for pathogens. (a) Bacterial enzymes can cleave structural transmembrane molecules of tight junctions; for example, the V. cholerae HA-protease cleaves the extracellular loops of occludin. (b) Several bacterial toxins and effector molecules target the peri-junctional actin cytoskeleton; for example, E. coli’s CNF-1 activates Rac1 and Cdc42 small GTPases at junctions. (c) Bacteria that translocate effector molecules into the host cell may target the AJC from the inside; for example, H. pylori’s CagA targets JAM and ZO-1 at the junctions as well as activating the c-met growth factor pathway. (d) Some bacteria target AJC components from the outside; for example, Listeria monocytogenes uses E-cadherin as a receptor for cell invasion, and activates the c-met receptor growth factor pathway. (e) Multiple viruses target the immunoglobulin superfamily at the AJC; for example, reovirus uses JAM as a receptor, adenovirus and coxsackievirus use CAR, and α-herpesviruses and poliovirus use nectins.