Human zonulin, a potential modulator of intestinal tight junctions

2000 ◽  
Vol 113 (24) ◽  
pp. 4435-4440 ◽  
Author(s):  
W. Wang ◽  
S. Uzzau ◽  
S.E. Goldblum ◽  
A. Fasano
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Ussing Chamber ◽  
Intestinal Lumen ◽  
Epithelial Surface ◽  
Ussing Chambers ◽  
Zonula Occludens ◽  
Surface Receptor ◽  
Dynamic Structures ◽  
Zonula Occludens Toxin

Intercellular tight junctions are dynamic structures involved in vectorial transport of water and electrolytes across the intestinal epithelium. Zonula occludens toxin derived from Vibrio cholerae interacts with a specific intestinal epithelial surface receptor, with subsequent activation of a complex intracellular cascade of events that regulate tight junction permeability. We postulated that this toxin may mimic the effect of a functionally and immunologically related endogenous modulator of intestinal tight junctions. Affinity-purified anti-zonula occludens toxin antibodies and the Ussing chamber assay were used to screen for one or more mammalian zonula occludens toxin analogues in both fetal and adult human intestine. A novel protein, zonulin, was identified that induces tight junction disassembly in non-human primate intestinal epithelia mounted in Ussing chambers. Comparison of amino acids in the active zonula occludens toxin fragment and zonulin permitted the identification of the putative receptor binding domain within the N-terminal region of the two proteins. Zonulin likely plays a pivotal role in tight junction regulation during developmental, physiological, and pathological processes, including tissue morphogenesis, movement of fluid, macromolecules and leukocytes between the intestinal lumen and the interstitium, and inflammatory/autoimmune disorders.

scholarly journals Symplekin, a novel type of tight junction plaque protein.

1996 ◽  
Vol 134 (4) ◽  
pp. 1003-1018 ◽  
Author(s):  
B H Keon ◽  
S Schäfer ◽  
C Kuhn ◽  
C Grund ◽  
W W Franke
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Sertoli Cells ◽  
Light And Electron Microscopy ◽  
Cell Types ◽  
Calculated Molecular Weight ◽  
Zonula Occludens ◽  
Cytoplasmic Face ◽  
Wide Range ◽  
Vascular Endothelia

Using a monoclonal antibody we have identified and cDNA-cloned a novel type of protein localized, by light and electron microscopy, to the plaque associated with the cytoplasmic face of the tight junction-containing zone (zonula occludens) of polar epithelial cells and of Sertoli cells of testis, but absent from the junctions of vascular endothelia. The approximately 3.7-kb mRNA encodes a polypeptide of 1142 amino acids (calculated molecular weight 126.5 kD, pI 6.25), for which the name "symplekin" (from Greek sigma upsilon mu pi lambda epsilon kappa epsilon iota, nu, to tie together, to weave, to be intertwined) is proposed. However, both the mRNA and the protein can also be detected in a wide range of cell types that do not form tight junctions or are even completely devoid of any stable cell contacts. Careful analyses have revealed that the protein occurs in all these diverse cells in the nucleoplasm, and only in those cells forming tight junctions is it recruited, partly but specifically, to the plaque structure of the zonula occludens. We discuss symplekin as a representative of a group of dual residence proteins which occur and probably function in the nucleus as well as in the plaques exclusive for either tight junctions, adherens junctions, or desmosomes.

Dissociation of ZO1-occludin complex is involved in zonula occludens toxin (Zot)-mediated disassembly of intestinal tight junctions

2001 ◽  
Vol 120 (5) ◽  
pp. A699
Author(s):  
Tammara L. Watts ◽  
Timothy D. Kiser ◽  
Regina A. Macatangay ◽  
Simeon E. Goldblum ◽  
Alessio Fasano
Keyword(s):  
Tight Junctions ◽  
Zonula Occludens ◽  
Zonula Occludens Toxin

Campylobacter jejuni inhibits the absorptive transport functions of Caco-2 cells and disrupts cellular tight junctions

Microbiology ◽  
2005 ◽  
Vol 151 (7) ◽  
pp. 2451-2458 ◽  
Author(s):  
Amanda MacCallum ◽  
Simon P. Hardy ◽  
Paul H. Everest
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Campylobacter Jejuni ◽  
Fluid Transport ◽  
Cell Function ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Ussing Chambers ◽  
Cell Monolayers ◽  
Junction Protein

Caco-2 cells are models of absorptive enterocytes. The net transport of fluid from apical to basolateral surfaces results in ‘domes' forming in differentiated monolayers. Here, the effect of Campylobacter jejuni on this process has been examined. C. jejuni caused no changes in short-circuit current upon infection of Caco-2 cell monolayers in Ussing chambers. Thus, no active secretory events could be demonstrated using this model. It was therefore hypothesized that C. jejuni could inhibit the absorptive function of enterocytes and that this may contribute to diarrhoeal disease. C. jejuni infection of fluid-transporting (‘doming’) Caco-2 cells resulted in a significant reduction in dome number, which correlated with a decrease in tight junction integrity in infected monolayers, when measured as transepithelial electrical resistance. Defined mutants of C. jejuni also reduced dome numbers in infected monolayers. C. jejuni also altered the distribution of the tight junction protein occludin within cell monolayers. The addition to monolayers of extracellular gentamicin prevented these changes, indicating the contribution of extracellular bacteria to this process. Thus, tight junction integrity is required for fluid transport in Caco-2 cell monolayers as leaky tight junctions cannot maintain support of transported fluid at the basolateral surface of infected cell monolayers. Inhibition of absorptive cell function, changes in epithelial resistance and rearrangement of tight junctional proteins such as occludin represent a potential diarrhoeal mechanism of C. jejuni.

Structure, biochemistry, and assembly of epithelial tight junctions

1987 ◽  
Vol 253 (6) ◽  
pp. C749-C758 ◽  
Author(s):  
B. Gumbiner
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Plasma Membranes ◽  
Freeze Fracture ◽  
Lateral Diffusion ◽  
Junctional Complex ◽  
Epithelial Cell Layer ◽  
Dependent Cell ◽  
Freeze Fracture Electron Microscopy ◽  
Dynamic Structures

The zonula occludens (ZO), also referred to as the tight junction, forms the barrier to the diffusion of molecules and ions across the epithelial cell layer through the paracellular space. The level of electrical resistance of the paracellular pathway seems to depend on the number of strands in the ZO observed by freeze-fracture electron microscopy (EM). The ZO also forms the boundary between the compositionally distinct apical and basolateral plasma membrane domains because it is a barrier to the lateral diffusion of lipids and membrane proteins that reside in the extracytoplasmic leaflet of the membrane bilayer. In contrast to its appearance in transmission EM, the tight junction is not a fusion between the outer membrane leaflets of neighboring cells. Rather it consists of protein molecules, including the newly discovered protein ZO-1 and probably others, which bring the plasma membranes into extremely close apposition so as to occlude the extracellular space. Very little is known about the assembly of tight junctions, but several kinds of evidence suggest that they are very dynamic structures. Other elements of the epithelial junctional complex including the zonula adherens (ZA), the Ca2+-dependent cell adhesion molecule uvomorulin, or L-CAM, and actin filaments of the cytoskeleton may participate in the assembly of the ZO.

scholarly journals Continuous endocytic recycling of tight junction proteins: how and why?

2012 ◽  
Vol 53 ◽  
pp. 41-54 ◽  
Author(s):  
Andrew D. Chalmers ◽  
Paul Whitley
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Dynamic Behaviour ◽  
Tight Junction Proteins ◽  
Tissue Remodelling ◽  
Extracellular Signals ◽  
Junctional Proteins ◽  
Cytoplasmic Proteins ◽  
Dynamic Structures ◽  
Junction Proteins

Tight junctions consist of many proteins, including transmembrane and associated cytoplasmic proteins, which act to provide a barrier regulating transport across epithelial and endothelial tissues. These junctions are dynamic structures that are able to maintain barrier function during tissue remodelling and rapidly alter it in response to extracellular signals. Individual components of tight junctions also show dynamic behaviour, including migration within the junction and exchange in and out of the junctions. In addition, it is becoming clear that some tight junction proteins undergo continuous endocytosis and recycling back to the plasma membrane. Regulation of endocytic trafficking of junctional proteins may provide a way of rapidly remodelling junctions and will be the focus of this chapter.

scholarly journals Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro.

1995 ◽  
Vol 96 (2) ◽  
pp. 710-720 ◽  
Author(s):  
A Fasano ◽  
C Fiorentini ◽  
G Donelli ◽  
S Uzzau ◽  
J B Kaper ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Tight Junctions ◽  
Actin Reorganization ◽  
Kinase C ◽  
Zonula Occludens ◽  
Zonula Occludens Toxin

Dissociation of ZO1-occludin complex is involved in zonula occludens toxin (Zot)-mediated disassembly of intestinal tight junctions

2001 ◽  
Vol 120 (5) ◽  
pp. A699-A699
Author(s):  
T WATTS ◽  
T KISER ◽  
R MACATANGAY ◽  
S GOLDBLUM ◽  
A FASANO
Keyword(s):  
Tight Junctions ◽  
Zonula Occludens ◽  
Zonula Occludens Toxin

scholarly journals Zonula Occludens Toxin Acts as an Adjuvant through Different Mucosal Routes and Induces Protective Immune Responses

2003 ◽  
Vol 71 (4) ◽  
pp. 1897-1902 ◽  
Author(s):  
Mariarosaria Marinaro ◽  
Alessio Fasano ◽  
Maria Teresa De Magistris
Keyword(s):  
Immune Responses ◽  
Tight Junctions ◽  
Mucosal Permeability ◽  
Mucosal Adjuvant ◽  
Promising Tool ◽  
Zonula Occludens ◽  
Specific Serum ◽  
Mucosal Vaccines ◽  
Zonula Occludens Toxin ◽  
Putative Binding Site

ABSTRACT Zonula occludens toxin (Zot) is produced by Vibrio cholerae and has the ability to increase mucosal permeability by reversibly affecting the structure of tight junctions. Because of this property, Zot is a promising tool for mucosal drug and antigen (Ag) delivery. Here we show that Zot acts as a mucosal adjuvant to induce long-lasting and protective immune responses upon mucosal immunization of mice. Indeed, the intranasal delivery of ovalbumin with two different recombinant forms of Zot in BALB/c mice resulted in high Ag-specific serum immunoglobulin G titers that were maintained over the course of a year. Moreover, His-Zot induced humoral and cell-mediated responses to tetanus toxoid in C57BL/6 mice and protected the mice against a systemic challenge with tetanus toxin. In addition, we found that Zot also acts as an adjuvant through the intrarectal route and that it has very low immunogenicity compared to the adjuvant Escherichia coli heat-labile enterotoxin. Finally, by using an octapeptide representing the putative binding site of Zot and of its endogenous analogue zonulin, we provide evidence that Zot may bind a mucosal receptor on nasal mucosa and may mimic an endogenous regulator of tight junctions to deliver Ags in the submucosa. In conclusion, Zot is a novel and effective mucosal adjuvant that may be useful for the development of mucosal vaccines.

Copper treatment alters the permeability of tight junctions in cultured human intestinal Caco-2 cells

1999 ◽  
Vol 277 (6) ◽  
pp. G1138-G1148 ◽  
Author(s):  
Simonetta Ferruzza ◽  
Maria-Laura Scarino ◽  
Giuseppe Rotilio ◽  
Maria Rosa Ciriolo ◽  
Paolo Santaroni ◽  
...  
Keyword(s):  
Tight Junction ◽  
Tight Junctions ◽  
Electrical Resistance ◽  
Transepithelial Electrical Resistance ◽  
Complete Medium ◽  
Zonula Occludens ◽  
Intracellular Effect ◽  
Tight Junction Permeability ◽  
Zonula Occludens 1 ◽  
Effect Of Copper

The effects of copper on tight-junction permeability were investigated in human intestinal Caco-2 cells, monitoring transepithelial electrical resistance and transepithelial passage of mannitol. Apical treatment of Caco-2 cells with 10–100 μM CuCl2(up to 3 h) produced a time- and concentration-dependent increase in tight-junction permeability, reversible after 24 h in complete medium in the absence of added copper. These effects were not observed in cells treated with copper complexed to l-histidine [Cu(His)2]. The copper-induced increase in tight-junction permeability was affected by the pH of the apical medium, as was the apical uptake of64CuCl2, both exhibiting a maximum at pH 6.0. Treatment with CuCl2produced a concentration-dependent reduction in the staining of F actin but not of the junctional proteins zonula occludens-1, occludin, and E-cadherin and produced ultrastructural alterations to microvilli and tight junctions that were not observed after treatment with up to 200 μM Cu(His)2for 3 h. Overall, these data point to an intracellular effect of copper on tight junctions, mediated by perturbations of the F actin cytoskeleton.

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