Alternative titles; symbols
HGNC Approved Gene Symbol: TJP1
Cytogenetic location: 15q13.1 Genomic coordinates (GRCh38): 15:29,699,367-29,969,049 (from NCBI)
Tight junctions, or zonula occludens, form regulated intercellular barriers between both epithelial and endothelial cells and serve to separate tissue compartments by limiting the ability of solutes, water, and immune cells to traverse the paracellular space. Tight junctions also separate biochemically distinct apical and basolateral plasma membrane surfaces and thereby contribute to the maintenance of cellular polarity. TJP1 is a peripheral membrane phosphoprotein expressed in tight junctions of both epithelial and endothelial cells. TJP1 is located on the cytoplasmic membrane surface precisely at sites of cell-cell contact (summary by Willott et al., 1993).
By sequencing partial cDNA clones obtained from a HepG2 human hepatoma cell line cDNA library, Willott et al. (1992) identified 2 splice variants of TJP1, which they called ZO1. The variants, ZO1-alpha-positive and ZO1-alpha-negative, differ in the inclusion or exclusion, respectively, of a 240-nucleotide sequence encoding an 80-amino acid motif that the authors called the alpha motif. RT-PCR detected variable expression of both variants in HepG2 cells and the colonic adenocarcinoma cell lines Caco-2 and T84. Western blot analysis detected the ZO1 isoforms at apparent molecular masses of about 223 kD and 214 kD. The ratio of expression of the 2 isoforms differed among the 3 cell lines. Immunohistochemical analysis showed that both ZO1 isoforms localized to tight junctions, and immunogold electron microscopy showed that both isoforms had indistinguishable mean distances from the plasma membrane.
Willott et al. (1993) cloned full-length ZO1 from human liver and HepG2 cDNA libraries. The deduced full-length 1,736-amino acid protein has a calculated molecular mass of 194.7 kD. It contains 3 N-terminal repeats of a 90-amino acid sequence, followed by an SRC (190090) homology-3 (SH3) domain, a central guanylate kinase (see 139270) domain, an acidic region, the alpha motif that is absent in the shorter ZO1 isoform, and a C-terminal proline-rich domain. The N-terminal half of ZO1, including the repeat motifs, SH3 domain, and guanylate kinase domain, shares significant homology with the Drosophila discs large tumor suppressor gene (see DLG1; 601014), rat Psd95 (DLG4; 602887), and human erythrocyte membrane protein p55 (MPP1; 305360). The guanylate kinase domain of ZO1 contains substitutions and a deletion that likely render it inactive. Northern blot analysis detected a major transcript of 7.9 kb in human liver and HepG2 cells.
By immunohistochemical analysis of adult rat tissues, Balda and Anderson (1993) found that Zo1-alpha-negative was expressed in tight junctions of all types of endothelial cells and of some highly specialized epithelial cells, such as seminiferous tubule Sertoli cells and renal glomerular podocytes. Zo1-alpha-positive was expressed in junctions of all typical transporting epithelial cells. There was no apparent correlation between electrical resistance and isoform expression. Balda and Anderson (1993) noted that ZO1-alpha-negative was generally expressed in junctions that were more structurally dynamic than those expressing ZO1-alpha-positive, suggesting that inclusion of the alpha motif may stabilize cell-cell junctions.
Using Northern and Western blot analyses, Nielsen et al. (2003) found that Zo1 mRNA and protein were highly expressed in mouse lens, with lower expression in testis, heart, brain, and kidney. Zo1 was detected at variable levels in all regions of mouse lens, with higher abundance in epithelial and differentiating cortical fiber cell layers than in nuclear fiber cells.
Using in vitro assays and immunoprecipitation studies, Itoh et al. (1999) showed that the mouse Tjp1, Tjp2 (607709), and Tjp3 (612689) PDZ1 domains interacted with the C-terminal cytoplasmic domains of Cldn1 (603718) through Cldn8 (611231). The mouse Tjp3 PDZ2 domain interacted with Tjp1, but showed no evidence of interaction with Tjp2. Itoh et al. (1999) concluded that Tjp3 may be recruited to the claudin-positive tight junctions through interactions with Tjp1 or claudin family members.
Helicobacter pylori translocates the protein CagA into gastric epithelial cells and has been linked to peptic ulcer disease and gastric carcinoma. Amieva et al. (2003) showed that injected CagA associates with the epithelial tight-junction scaffolding protein ZO-1 and the transmembrane protein junctional adhesion molecule (JAM1; 605721), causing an ectopic assembly of tight junction components at sites of bacterial attachment, and altering the composition and function of the apical-junctional complex. Long-term CagA delivery to polarized epithelia caused a disruption of the epithelial barrier function and dysplastic alterations in epithelial cell morphology. CagA appears to target H. pylori to host cell intercellular junctions and to disrupt junction-mediated functions.
D'Atri et al. (2002) found that overexpression of Xenopus cingulin (CGN; 609473) in transfected Xenopus epithelial cells resulted in disruption of endogenous Zo1 localization, suggesting that the proteins functionally interact.
Using coimmunoprecipitation analysis, Nielsen et al. (2003) found that Zo1 interacted with the gap junction connexins Cx46 (GJA3; 121015) and Cx50 (GJA8; 600897) in mouse lens fiber cells. Mutation analysis revealed that the second PDZ domain of Zo1 interacted with C-terminal isoleucines of Cx46 and Cx50.
Tang et al. (2008) investigated the effects of alcohol on miR212 (613487) and on expression of its predicted target, ZO1, and studied the role of miR212 in the pathophysiology of alcoholic liver disease in humans. They found that alcohol increased miR212 expression, decreased ZO1 protein levels, disrupted tight junctions, and increased the permeability of monolayers of Caco2 human intestinal epithelial cells. Overexpression of miR212 was correlated with hyperpermeability of the monolayer barrier. Levels of miR212 were higher, and protein levels of ZO1 were lower, in colon biopsy samples of patients with alcoholic liver disease compared with healthy controls. Tang et al. (2008) concluded that ethanol induces miR212 overexpression, which causes gut leakiness by downregulating ZO1 translation.
Using yeast 2-hybrid analysis, Huo et al. (2011) found that GRINL1A combined protein-1 (GCOM1; 614071) and MRCK-beta (CDC42BPB; 614062) bound the C-terminal ZU5 domain of ZO1. Binding of ZU5 by the isolated N-terminal interacting peptide from GCOM1 caused a conformational change in the ZU5 domain. GCOM1 targeted ZO1 to junctional membranes in polarized MDCK cells. The ZU5 domain of ZO1 was required for targeting of MRCK-beta to the leading edge of migrating COS-7 cells. Disruption of the ZO1/MRCK-beta complex inhibited MRCK-beta-mediated cell migration.
By fluorescence in situ hybridization using a cDNA probe, Mohandas et al. (1995) mapped the TJP1 gene to chromosome 15q13. The Jackson Laboratory backcross DNA panel derived from interspecies crosses was used to map Tjp1 to mouse chromosome 7 in a region with conserved homology to 15q13. Fluorescence in situ hybridization studies on metaphases from patients with the Prader-Willi syndrome (176270) and/or the Angelman syndrome (105830) showed that TJP1 maps close but distal to the PWS/AS chromosome region.
Katsuno et al. (2008) found that Tjp1 +/- mice showed no obvious phenotypes and had fertility and growth rates comparable to those of wildtype mice. However, Tjp1 -/- embryos were lost in midgestation. At around embryonic days 9.5 and 10.5, Tjp1 -/- embryos showed severe growth defects, including reduced size and absence of turning, that were associated with abnormal apoptosis. Chorioallantoic fusion did not occur in Tjp1 -/- embryos, and Tjp1 -/- yolk sacs showed abnormal vascularization. In placenta, the labyrinth layer of Tjp1 -/- embryos lacked immature embryonic nucleated erythrocytes and blood vessels derived from embryonic mesoderm.
Amieva, M. R., Vogelmann, R., Covacci, A., Tompkins, L. S., Nelson, W. J., Falkow, S. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 300: 1430-1434, 2003. [PubMed: 12775840] [Full Text: https://doi.org/10.1126/science.1081919]
Balda, M. S., Anderson, J. M. Two classes of tight junctions are revealed by ZO-1 isoforms. Am. J. Physiol. 264: C918-C924, 1993. [PubMed: 7682777] [Full Text: https://doi.org/10.1152/ajpcell.1993.264.4.C918]
D'Atri, F., Nadalutti, F., Citi, S. Evidence for a functional interaction between cingulin and ZO-1 in cultured cells. J. Biol. Chem. 277: 27757-27764, 2002. [PubMed: 12023291] [Full Text: https://doi.org/10.1074/jbc.M203717200]
Huo, L., Wen, W., Wang, R., Kam, C., Xia, J., Feng, W., Zhang, M. Cdc42-dependent formation of the ZO-1/MRCK-beta complex at the leading edge controls cell migration. EMBO J. 30: 665-678, 2011. [PubMed: 21240187] [Full Text: https://doi.org/10.1038/emboj.2010.353]
Itoh, M., Furuse, M., Morita, K., Kubota, K., Saitou, M., Tsukita, S. Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins. J. Cell Biol. 147: 1351-1363, 1999. [PubMed: 10601346] [Full Text: https://doi.org/10.1083/jcb.147.6.1351]
Katsuno, T., Umeda, K., Matsui, T., Hata, M., Tamura, A., Itoh, M., Takeuchi, K., Fujimori, T., Nabeshima, Y., Noda, T., Tsukita, S., Tsukita, S. Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells. Molec. Biol. Cell 19: 2465-2475, 2008. [PubMed: 18353970] [Full Text: https://doi.org/10.1091/mbc.e07-12-1215]
Mohandas, T. K., Chen, X.-N., Rowe, L. B., Birkenmeier, E. H., Fanning, A. S., Anderson, J. M., Korenberg, J. R. Localization of the tight junction protein gene TJP1 to human chromosome 15q13, distal to the Prader-Willi/Angelman region, and to mouse chromosome 7. Genomics 30: 594-597, 1995. [PubMed: 8825647] [Full Text: https://doi.org/10.1006/geno.1995.1281]
Nielsen, P. A., Baruch, A., Shestopalov, V. I., Giepmans, B. N. G., Dunia, I., Benedetti, E. L., Kumar, N. M. Lens connexins alpha-3-Cx46 and alpha-8-Cx50 interact with zonula occludens protein-1 (ZO-1). Molec. Biol. Cell 14: 2470-2481, 2003. [PubMed: 12808044] [Full Text: https://doi.org/10.1091/mbc.e02-10-0637]
Tang, Y., Banan, A., Forsyth, C. B., Fields, J. Z., Lau, C. K., Zhang, L. J., Keshavarzian, A. Effect of alcohol on miR-212 expression in intestinal epithelial cells and its potential role in alcoholic liver disease. Alcohol. Clin. Exp. Res. 32: 355-364, 2008. [PubMed: 18162065] [Full Text: https://doi.org/10.1111/j.1530-0277.2007.00584.x]
Willott, E., Balda, M. S., Fanning, A. S., Jameson, B., Van Itallie, C., Anderson, J. M. The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppressor protein of septate junctions. Proc. Nat. Acad. Sci. 90: 7834-7838, 1993. [PubMed: 8395056] [Full Text: https://doi.org/10.1073/pnas.90.16.7834]
Willott, E., Balda, M. S., Heintzelman, M., Jameson, B., Anderson, J. M. Localization and differential expression of two isoforms of the tight junction protein ZO-1. Am. J. Physiol. 262: C1119-C1124, 1992. [PubMed: 1590354] [Full Text: https://doi.org/10.1152/ajpcell.1992.262.5.C1119]