Breaking into the epithelial apical–junctional complex — news from pathogen hackers
Introduction
The apical–junctional complex (AJC) is a highly specialized structure at the apical tip of the lateral membrane of polarized epithelial cells. In addition to its multi-faceted participation in regulating cell–cell adhesion between neighboring cells, integrity of the epithelial barrier, and contractile forces during morphogenesis and wound healing, the AJC is equally important as a hub for signaling pathways controlling cell proliferation, cell differentiation and cell polarity [1]. This signaling hub consists of complex networks of interconnected proteins that dynamically interact with each other to adjust and coordinate different cellular functions. Defects in one component of the junction often lead to changes in the entire AJC 2., 3., 4..
Pathogens have exploited the AJC as a strategy for overcoming the epithelial barrier and as a site for host colonization. They have evolved mechanisms to directly break down tight junction barriers to allow entry into, or exit from, a host organism, and to co-opt nutrients from the interstitium. Remarkably, they have also been able to access receptors hidden on the basal–lateral epithelial membrane to enter cells where they may replicate or seek protection from the immune system. Pathogenic microbes have even found ways to benefit from inflammation, increased cell turnover and prevention of wound healing, all of which are controlled to some extent by the AJC [5] (Figure 1).
The AJC contains several distinct protein sub-complexes. In general, each protein sub-complex consists of a transmembrane protein bound to scaffolding proteins, each of which has multiple protein–protein binding motifs that potentially link together different membrane sub-complexes. Scaffold proteins generally bind to the actin cytoskeleton, although links to microtubules may also be present 1., 6.. The cadherin/catenin and claudin/occludin/ZO (zonula occludens) protein sub-complexes form the adherens and tight junctions, respectively, and together with the cytoskeleton provide the basic structural components of the AJC 7., 8.. Of course, there are many regulatory elements that control the dynamic organization of the AJC and co-ordinate its many functions (Figure 2).
Here, we review some of the strategies pathogens use to interact with the structural and regulatory components of the AJC. In particular, microbial virulence gene products point to an emerging role for a family of receptors belonging to the Ig superfamily as important regulators of the AJC. Focusing on these targets, we review what is known about the molecular regulation of the AJC by Ig superfamily receptors during junction assembly. The results of this work give us as much information about AJC structure and function as about microbial pathogenesis.
Section snippets
Cleaving structural components
Bacterial pathogens have developed strategies to interfere with structural components of the AJC at the level of transmembrane proteins, scaffolding proteins and the cytoskeleton. Perhaps the simplest strategy used by pathogens is to secrete one or more enzymes that target the extracellular domain of AJC transmembrane proteins. This usually leads to barrier defects and disruption of the epithelial monolayer [9]. For example, Bacteroides fragilis secretes the toxin Fragilysin that cleaves the
Ig superfamily members as regulatory elements of the apical–junctional complex
Why have so many unrelated viral and bacterial factors such as CagA evolved to target the Ig superfamily at the AJC? Under physiological conditions, Ig superfamily receptors are implicated in controlling the disassembly and re-assembly of adherens and tight junctions in the AJC. For example, migration of leukocytes across cell monolayers requires the local opening of intercellular junctions. Live cell imaging of neutrophils migrating through an endothelial monolayer showed that GFP-labeled
Conclusions
The AJC is a signaling hub regulating many important cellular functions. It comprises basic structural components, including the cadherin/catenin and claudin/occludin complexes that form the adherens and tight junctions, respectively, and the cytoskeleton, which connects these junctions into an integrated network. Regulatory sub-complexes comprising transmembrane receptors of the Ig superfamily resemble a software operating system, and may control the organization of the structural components
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
Because of space constraints we have included examples of a limited number of pathogens and their targets rather than attempting to be complete. We apologize to the many investigators whose work we were unable to cite. Work from the Nelson and Falkow laboratory is supported by a Walter V and Idun Y Berry Fellowship (RV); Deutsche Forschungsgemeinschaft Fellowship VO 864/1-1 (RV); a Pediatric Infections Disease Society of America/St. Jude Fellowship in Pediatric Infectious Diseases (MRA); and
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