Breaking into the epithelial apical–junctional complex — news from pathogen hackers

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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.

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:

  • of special interest

  • ••

    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

References (59)

  • S. Ohno

    Intercellular junctions and cellular polarity: the PAR–aPKC complex, a conserved core cassette playing fundamental roles in cell polarity

    Curr Opin Cell Biol

    (2001)
  • E.S. Wittchen et al.

    Exogenous expression of the amino-terminal half of the tight junction protein ZO-3 perturbs junctional complex assembly

    J Cell Biol

    (2000)
  • E. Knust et al.

    Composition and formation of intercellular junctions in epithelial cells

    Science

    (2002)
  • K. Matter et al.

    Signalling to and from tight junctions

    Nat Rev Mol Cell Biol

    (2003)
  • P. Humbert et al.

    Dlg, Scribble and Lgl in cell polarity, cell proliferation and cancer

    Bioessays

    (2003)
  • S. Falkow

    Cellular microbiology is launched

    Cell Microbiol

    (1999)
  • W.J. Nelson

    Adaptation of core mechanisms to generate cell polarity

    Nature

    (2003)
  • S. Tsukita et al.

    Multifunctional strands in tight junctions

    Nat Rev Mol Cell Biol

    (2001)
  • C. Jamora et al.

    Intercellular adhesion, signalling and the cytoskeleton

    Nat Cell Biol

    (2002)
  • J. Berkes et al.

    Intestinal epithelial responses to enteric pathogens: effects on the tight junction barrier, ion transport and inflammation

    Gut

    (2003)
  • S. Wu et al.

    Bacteroides fragilis enterotoxin cleaves the zonula adherens protein, E-cadherin

    Proc Natl Acad Sci U S A

    (1998)
  • Z. Wu et al.

    Distinct effects of Vibrio cholerae haemagglutinin/protease on the structure and localization of the tight junction-associated proteins occludin and ZO-1

    Cell Microbiol

    (2000)
  • Y. Hanakawa et al.

    Molecular mechanisms of blister formation in bullous impetigo and staphylococcal scalded skin syndrome

    J Clin Invest

    (2002)
  • A.M. Hopkins et al.

    Constitutive activation of Rho proteins by CNF-1 influences tight junction structure and epithelial barrier function

    J Cell Sci

    (2003)
  • A. Nusrat et al.

    Clostridium difficile toxins disrupt epithelial barrier function by altering membrane microdomain localization of tight junction proteins

    Infect Immun

    (2001)
  • L. Van Aelst et al.

    Role of Rho family GTPases in epithelial morphogenesis

    Genes Dev

    (2002)
  • S. Etienne-Manneville et al.

    Rho GTPases in cell biology

    Nature

    (2002)
  • R. Yuhan et al.

    Enteropathogenic Escherichia coli-induced myosin light chain phosphorylation alters intestinal epithelial permeability

    Gastroenterology

    (1997)
  • I. Simonovic et al.

    Enteropathogenic Escherichia coli dephosphorylates and dissociates occludin from intestinal epithelial tight junctions

    Cell Microbiol

    (2000)
  • Cited by (0)

    Co-first authors

    View full text