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Molecular Structure of Tight Junctions and Their Role in Epithelial Transport

James Melvin Anderson

J. M. Anderson is a Professor of Medicine and Cell Biology at the Yale School of Medicine, New Haven, Connecticut 06520-8019.

	Abstract

 
Tight junctions create a paracellular barrier with physiological properties that differ among epithelia. Among these differences are electrical resistance and discrimination for solute size and charge. Emerging evidence suggests that a large family of transmembrane proteins called the claudins create these variable properties.

	Introduction

Top Introduction Morphology of tight junctions... Aqueous "pores" in the... Molecular components of the... Do claudins create the... What is the role... Conclusions References

 
Tight junctions create the major barrier regulating paracellular movement of water and solutes across vertebrate epithelia. This barrier is variable and physiologically regulated, and its disruption contributes to human diseases (13, 15). This review will first briefly define the basic physiological properties and morphological features of the tight junction. These have been known for decades but lacked a molecular explanation. The evidence will be presented that a large family of transmembrane proteins called the claudins, and to a lesser extent a single gene product called occludin, are responsible for these properties.

	Morphology of tight junctions and their role in epithelial transport

Top Introduction Morphology of tight junctions... Aqueous "pores" in the... Molecular components of the... Do claudins create the... What is the role... Conclusions References

 
Epithelial transport occurs through both transcellular and paracellular pathways (Fig. 1). Transcellular transport is directional, energy dependent, and governed by the cell-specific profile of transporters and channels positioned on the apical and basolateral cell membranes. In contrast, paracellular transport is passive and results from diffusion, electrodiffusion, or osmosis down the gradients created by transcellular mechanisms. The paracellular route does not show directional discrimination; however, it varies enormously among epithelia in terms of electrical resistance and shows small differences in ionic selectivities (Table 1). Thus the paracellular pathway complements transcellular mechanisms by defining the degree and selectivity of back leak for ions and solutes, making an important tissue-specific contribution to overall transport (Table 1) (2, 15). In some cases, the lateral intercellular space can influence paracellular electrical resistance; however, the tight junction is the major physical structure defining the specific properties of the paracellular barrier.

View larger version (24K): [in this window] [in a new window]   FIGURE 1. Transepithelial transport pathways. The transcellular route is both active and passive and based on the activity of transmembrane pumps, channels, and carriers expressed in a polarized fashion. Paracellular transport is only passive and driven by the gradients secondary to transcellular transport mechanisms. The major barrier in the paracellular route is the tight junction, which is regulated and varies among epithelia in tightness and ion selectivity. This regulated back diffusion can significantly modify the molecular composition of transcellular transport.

View larger version (157K): [in this window] [in a new window]   FIGURE 2. Freeze-fracture electron micrograph of tight junction strands in rat liver. Tissue was frozen in liquid nitrogen, cracked, and shadowed with vaporized platinum. The fracture plane divides the lipid bilayer of the plasma membrane, revealing continuous rows of transmembrane protein particles spaced at 18 nm. Protein particles from adjacent cells meet in the intercellular space to create the barrier. Claudins are the major structural protein creating the particles and strands. (Image provided by Christoph Rahner, Yale University and Institute of Anatomy, Basel).

View larger version (20K): [in this window] [in a new window]   FIGURE 3. Schematic interpretation of how tight junction transmembrane protein particles (Fig. 2) create continuous strands and intercellular contacts to create the paracellular barrier. The 10-nm size suggests that each particle is an oligomer of claudin monomers. Both claudins and occludin are homophilic cell-cell adhesion molecules, and some claudins can form heterophilic adhesions with other claudins. Presumably the extracellular contacts of these proteins create the aqueous spaces capable of size and ionic discrimination. The first (NH2 terminal) extracellular loop of claudins averages ~54 residues and the second 23. The first and second loops of human occludin are 46 and 48 residues, respectively.

	Aqueous "pores" in the tight junction exhibit size and charge selectivity

Top Introduction Morphology of tight junctions... Aqueous "pores" in the... Molecular components of the... Do claudins create the... What is the role... Conclusions References

	Molecular components of the tight junction

Top Introduction Morphology of tight junctions... Aqueous "pores" in the... Molecular components of the... Do claudins create the... What is the role... Conclusions References

 
Since identification in 1986 of zonula occludens (ZO)-1 as the first tight junction-associated protein (20), almost 30 additional proteins have been described (reviewed in Ref. 13). They can be grouped into four major categories. First are the peripherally associated scaffolding proteins like ZO-1 (ZO-2, ZO-3, AF6, and cingulin) that appear to organize the transmembrane proteins and couple them to other cytoplasmic proteins and to actin microfilaments. Second are numerous "signaling" proteins proposed to be involved in junction assembly, barrier regulation, gene transcription, and perhaps other, presently undefined pathways. Third are proteins likely to regulate membrane vesicle targeting, such as sec6/8 and the occludin-binding protein VAMP-associated protein (VAP-33). Last, there are three known transmembrane proteins, junction adhesion molecule (JAM), occludin, and claudin. These are obviously the most likely candidates for creating the paracellular barrier. JAM is a member of the immunoglobulin superfamily and may be involved in immune cell transmigration or cell adhesion (3) but has not been localized to the junction strands. Claudin and occludin were both discovered and characterized by Tsukita and associates (5). This work has had a profound impact on our understanding of the molecular basis of the paracellular barrier and the direction of future research.

	Do claudins create the barrier?

Top Introduction Morphology of tight junctions... Aqueous "pores" in the... Molecular components of the... Do claudins create the... What is the role... Conclusions References

 
Both circumstantial and limited direct experimental evidence support the notion that claudins create the variable properties of the barrier. There exist at least 20 claudin genes encoding proteins that range from ~20 to 27 kDa, with primary sequence identity as low as 12% (5, 13). They are predicted to have four transmembrane-spanning helices with cytoplasmic NH₂ and COOH terminals (Fig. 3). A few reports have described that some claudins have very restricted expression patterns. For example, claudin-5 is predominately expressed in tight junctions of endothelial cells (14), and claudin-11 is the only claudin expressed in tight junctions that show linear non-cross-linked fibrils [e.g., Sertoli cells, oligodendrocytes, and epithelial cells of the organ of Corti (9)]. Claudin-16 (a.k.a. paracellin-1) is limited in the adult to tight junctions of the thick ascending loop of Henle (TALH) in the kidney (18). Thus, consistent with a role in providing diversity, there are many different claudins and they show distinct expression patterns.

There is excellent evidence that claudins are both sufficient and necessary to form the junction strands. When individual claudins are expressed by transfection in junction-null fibroblasts, they assemble into long strands of 10-nM particles and the strands adhere between cells (7). According to a study of a limited number of claudins (8), they all are capable of homophilic adhesion between cells, and some but not all pairs are capable of heterophilic adhesion. This raises the interesting question of how many claudins compose a tight junction particle and whether a single particle contains more than one type of claudin (Fig. 3). The particle size is similar to that observed for gap junctions. Each gap junction particle represents a complex of six connexin proteins with a total mass of ~200 kDa. By comparison, this strongly suggests that particles within the tight junction are also multimeric complexes of claudins. With 20 claudins, the combinatorial possibilities for particle structure and function are very large. It is of note that different claudins create slightly different fibril morphology when expressed in fibroblasts, suggesting that the specific combination of claudins expressed in each epithelial cell type creates the variable morphology observed in vivo (8). The necessity of claudins for strand formation in vivo is supported by the phenotype of claudin-11 knockout mice. As mentioned above, claudin-11 is found in junctions with parallel, nonbranched strands, such as in oligodendrocytes in the central nervous system and in Sertoli cells in the testis. When claudin-11 is deleted in mice through homologous recombination, tight junctions are absent in these specific cell types. As a functional correlate, the mice show both central nervous system nerve conduction delays and male sterility (9). Together these results provide strong evidence that claudins are the principal structural element of the fibrils, define fibril morphology, and show selectivity in formation of adhesive contacts in the extracellular space.

Only a few studies have directly addressed claudin(s) function. Two groups have reported (10, 11) that overexpression of claudin-1 in MDCK cell monolayers increases the transepithelial electrical resistance; one of these groups also showed a simultaneous and seemingly paradoxical increase in the flux for mannitol and FITC-dextran (11). Others have shown that some claudins are receptors for a cytotoxic protein toxin produced by the bacterium C. perfringens (CPE). A noncytotoxic fragment of the CPE protein is capable of binding claudin-4 in MDCK cells, resulting in its selective removal from the junction and a drop in paracellular electrical resistance (19).

The most direct evidence that claudins have a functional role comes from the phenotype of mutations in human claudin-16, the basis of recessive renal hypomagnesemia and hypercalcuria (18). The major site for regulating Mg²⁺ is the TALH; coincidentally, this is the principal site where claudin-16 is expressed. Active transcellular transport generates a positive intraluminal electrical potential within the TALH with respect to the interstitial space. This electrical potential difference forces efflux of cations (Na⁺, Mg²⁺, and Ca²⁺) from the tubule through the tight junction. In affected individuals, Mg²⁺ does not exit the tubule in the TALH and is lost in the urine, resulting in hypomagnesemia and presenting as weakness and seizures in childhood. The disease phenotype can be rationalized by proposing that claudin-16 normally creates a cation-selective or permissive pore through the tight junction. The Na⁺ and Ca²⁺ levels are less affected because, unlike Mg²⁺, they undergo transport at other renal tubule sites under hormonal control. Coincidentally, the extracellular amino acid side chains of claudin-16 are among the most acidic of all claudins; others have a net neutral or basic composition. It is tempting to speculate that extracellular loops of the claudins position their variable residues to influence passage of ions through the aqueous spaces (Fig. 3).

	What is the role of occludin in the barrier?

Top Introduction Morphology of tight junctions... Aqueous "pores" in the... Molecular components of the... Do claudins create the... What is the role... Conclusions References

 
Although occludin was discovered several years before the claudins, its function remains unclear. Like the claudins, it spans the membrane four times and shows homophilic intercellular adhesion. Unlike claudins, it is not by itself sufficient to form a tight junction, since when expressed in fibroblasts it forms only short aggregates. However, it appears to interact, directly or indirectly, with claudin and is recruited into the long strands formed by coexpression of a claudin (8). Consistent with the transfection results, in epithelial cells in vivo occludin can be found within freeze-fractured strands as well as on the lateral cell membrane where there are no strands (6). Several groups have reported that its overexpression in cultured MDCK epithelial cells induces a modest increase in transepithelial electrical resistance as well as an increase in the flux of noncharged solutes (1, 12). These seemingly contradictory effects, similar to those observed when claudin-1 is overexpressed, are difficult to explain unless the barrier discriminates differently for charged and noncharged molecules. The extracellular sequences of occludin lack charged amino acid side chains and have an unusually high content of tyrosine and glycine (6), making it difficult to envision a direct role for occludin in defining charge selectivity. Conceivably, occludin could increase electrical resistance by influencing the extracellular conformation of charged residues of claudins. Ultimately, occludin is a facultative component of the barrier since it is absent from some junctions in vivo and its deletion from embryonic stem cells through homologous recombination interferes neither with formation of strands nor of a functional paracellular barrier (17).

	Conclusions

Top Introduction Morphology of tight junctions... Aqueous "pores" in the... Molecular components of the... Do claudins create the... What is the role... Conclusions References

 
Provocative but currently incomplete evidence supports speculation that the claudin family is responsible for creating the tight junction barrier and the variable properties of paracellular transport. Proof will require more detailed characterization and correlation of the structure and physiology of individual claudins. This will likely come from both genetic manipulation of claudins in mice and physiological study of claudin in various expression systems. It will be important to determine whether, and how, the 20 different claudins confer different solute and charge selectivity. Ultimately, the answer to this question will require determination of the three-dimensional structure of the extracellular sequences to visualize how they form pores.

It remains unclear how cells regulate paracellular permeability in the short and long term. Now we can begin to ask whether some of these changes are based in posttranslational modifications of claudins or alteration of their protein levels through transcriptional mechanisms.

It is also unknown whether claudins, or related proteins, are expressed in Drosophila or Caenorhabditis elegans; if they are, then genetic methods will greatly facilitate their study. The phenotype of mutations in human claudin-16 provided a striking insight into the physiological role of claudins and raises the possibility that there are additional claudin mutations or polymorphisms that present as epithelial diseases.

Finally, we should keep in mind the possibility that additional proteins that control paracellular permeability remain to be discovered. Despite these many questions, recent insights into the molecular structure of tight junctions are beginning to explain their important physiological differences and contribution to paracellular transport.

	References

Top Introduction Morphology of tight junctions... Aqueous "pores" in the... Molecular components of the... Do claudins create the... What is the role... Conclusions References

 

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