Gene expression of the tight junction protein occludin includes differential splicing and alternative promoter usage

Mankertz, Joachim; Waller, Jörg Stefan; Hillenbrand, Bernd; Tavalali, Shida; Florian, Peter; Schöneberg, Torsten; Fromm, Michael; Schulzke, Jörg D.

doi:10.1016/s0006-291x(02)02487-7

Cited by 59 publications

(53 citation statements)

References 35 publications

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“…This is consistent with previous observations that the GuK domain is involved in occludin binding (8). Occludin splice variants, where the C terminus is located extracellular instead of intracellular due to a lack of transmembrane domain four, were not localized at TJ (30). Occludin mutants without the intracellular C terminus were shown to disrupt TJ (31).…”

Section: Discussionsupporting

confidence: 92%

The Tight Junction Protein Occludin and the Adherens Junction Protein α-Catenin Share a Common Interaction Mechanism with ZO-1

Müller

Portwich

Schmidt

et al. 2005

Journal of Biological Chemistry

148

150

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The exact sites, structures, and molecular mechanisms of interaction between junction organizing zona occludence protein 1 (ZO-1) and the tight junction protein occludin or the adherens junction protein ␣-catenin are unknown. Binding studies by surface plasmon resonance spectroscopy and peptide mapping combined with comparative modeling utilizing crystal structures led for the first time to a molecular model revealing the binding of both occludin and ␣-catenin to the same binding site in ZO-1. Our data support a concept that ZO-1 successively associates with ␣-catenin at the adherens junction and occludin at the tight junction. Strong spatial evidence indicates that the occludin C-terminal coiled-coil domain dimerizes and interacts finally as a four-helix bundle with the identified structural motifs in ZO-1. The helix bundle of occludin 406 -521 and ␣-catenin Different junctional complexes such as adherens junctions and, in specialized tissues, tight junctions, gap junctions, and desmosomes connect cells in multicellular organisms. TJ 1 seal the most apical-lateral parts of cells and constitute a diffusion barrier for the paracellular flow of molecules and serve as a fence between the apical and basolateral membrane compartment (1). In contrast, AJ play important roles in cell adhesion, migration, morphogenesis, and proliferation. AJ represent Ca 2ϩ -dependent cell-cell contacts localized basolateral of TJ, where transmembrane proteins of the cadherin family mediate adhesion. Assembly of AJ is a prerequisite for the formation of TJ and desmosomes (2). ␤-and ␣-catenin bind to the cadherin cytoplasmic domain and link the cadherin-catenin complex to the F-actin cytoskeleton. An important scaffolding protein in cell-cell contacts is the zona occludens protein 1. ZO-1 is a membrane associated guanylate kinase homologue protein composed of the following domains: three PDZ (PSD95/Dlg/ZO-1), a SH3, a GuK (3), an actin binding region (4), and a ZU5 (ZO-1 and Unc5-like netrin receptor domain) according SMART (Simple Modular Architecture Research Tool (smart.embl-heidelberg.de) data base (5)). In non-epithelial cells ZO-1 is a major component of AJ, whereas in epithelial cells it is localized at TJ by directly binding to claudins (6). Occludin, one of the transmembrane proteins of TJ, is a multiphosphoprotein involved in regulation of TJ (7). It has four transmembrane domains with two extracellular loops and a cytosolic N and C terminus. A sequence of 244 amino acids in human ZO-1 containing the GuK domain and an acidic region C terminus to GuK binds to the complete intracellular C-terminal tail of chicken occludin (8).ZO-1 also binds to the AJ protein ␣-catenin (9) and to connexins in gap junctions (10), indicating a general scaffolding function of ZO-1 in junctional complexes. ␣-Catenin consists of several four-helix-bundle domains (vinculin homology domains, VH1-3) and binds ␤-catenin via an intermolecular helix bundle mechanisms within the E-cadherin-catenin complex at the intracellular side of AJ, where one helix of ...

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Section: Discussionsupporting

confidence: 92%

The Tight Junction Protein Occludin and the Adherens Junction Protein α-Catenin Share a Common Interaction Mechanism with ZO-1

Müller

Portwich

Schmidt

et al. 2005

Journal of Biological Chemistry

148

150

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“…We also detected expression of the previously described splicing form with deletion of exon 4 (OCLNex4del) (10). However, we did not observe expression of other splicing forms previously detected in cell lines with deletion of exon 9, deletion of exons 4 through 7, and partial deletion of exon 6 (data not shown) (5,9).…”

Section: Resultssupporting

confidence: 44%

“…We hypothesized that splicing diversity, generating multiple functionally distinct OCLN protein isoforms, might modulate susceptibility to HCV infection. Six splicing forms of OCLN and two distinct promoters, P1 and P2, have been described in cell lines (4,5,9,10,13). In the present study, we explored the splicing diversity of OCLN in normal human liver and observed variable expression of known and novel isoforms.…”

Section: Persistent Hepatitis C Virus (Hcv) Infection Is a Primary Etmentioning

confidence: 87%

Splicing Diversity of the Human OCLN Gene and Its Biological Significance for Hepatitis C Virus Entry

Kohaar

Ploß

Korol

et al. 2010

J Virol

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Persistent hepatitis C virus (HCV) infection is a primary etiological factor for the development of chronic liver disease, including cirrhosis and cancer. A recent study identified occludin (OCLN), an integral tight junction protein, as one of the key factors for HCV entry into cells. We explored the splicing diversity of OCLN in normal human liver and observed variable expression of alternative splice variants, including two known forms (WT-OCLN and OCLN-ex4del) and six novel forms (OCLN-ex7ext, OCLNex3pdel, OCLN-ex3del, OCLN-ex3-4del, OCLN-ex3p-9pdel, and OCLN-ex3p-7pdel). Recombinant protein isoforms WT-OCLN and OCLN-ex7ext, which retained the HCV-interacting MARVEL domain, were expressed on the cell membrane and were permissive for HCV infection in in vitro infectivity assays. All other forms lacked the MARVEL domain, were expressed in the cytoplasm, and were nonpermissive for HCV infection. Additionally, we observed variable expression of OCLN splicing forms across human tissues and cell lines. Our study suggests that the remarkable natural splicing diversity of OCLN might contribute to HCV tissue tropism and possibly modify the outcome of HCV infection in humans. Genetic factors crucial for regulation of OCLN expression and susceptibility to HCV infection remain to be elucidated.Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver, the fifth most common malignancy worldwide, and the third leading cause of cancer-related death, after cancers of lung and stomach (WHO Mortality Database [http://www.who.int/healthinfo/morttables/en/index.html]). The estimated incidence of new HCC cases is about 500,000 to 1,000,000 annually, with mortality of 600,000 cases per year on a global scale (12,16,17,20,24). Various risk factors for HCC include infection with hepatitis C virus (HCV) or hepatitis B virus (HBV), toxic exposures (alcohol and aflatoxins), metabolic disease (diabetes, nonalcoholic fatty liver disease, and hereditary hemochromatosis), and immune-related conditions such as primary biliary cirrhosis and autoimmune hepatitis (15).The only established in vivo model for the study of HCV infection in an immunocompetent host is the chimpanzee (23). The inability of HCV to infect animals other than humans and chimpanzees has severely hampered efforts in developing a useful small animal model for the disease, specific antiviral therapies, and an effective vaccine against HCV-mediated liver cancer (18,23).In the United States, chronic HCV infection is the major etiological agent of liver cancer. Among individuals infected with HCV, approximately 80% develop chronic HCV infection, of which 20% will progress to cirrhosis, and 1 to 5% will progress to liver cancer (14). Genetic factors might affect the risk of liver cancer by modifying the susceptibility to HCV infection and viral clearance. Recent studies identified occludin (OCLN), an integral tight junction (TJ) protein, as one of the key factors for HCV entry into cells (8,18). HCV infectivity was exclusively mediated by the second extracell...

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“…TNF-␣ and IFN-␥ induce internalization of the TJ proteins occludin, claudin-1, claudin-4, and junctional adhesion molecule-1 (JAM-1) in intestinal T84 epithelial cells (8). Additionally, TNF-␣ and IFN-␥ decrease occludin gene expression in human colonic HT-29/B6 cells (39,40) and reduce the expression of zonula occludens-1 (ZO-1) and JAM-1 in primary human airway cells (12). Furthermore, TNF-␣ decreases claudin-1 expression and causes ZO-1 redistribution in Madin-Darby canine kidney epithelial cells (55).…”

mentioning

confidence: 99%

Proinflammatory cytokines tumor necrosis factor-α and interferon-γ alter tight junction structure and function in the rat parotid gland Par-C10 cell line

Baker¹,

Camden²,

Redman³

et al. 2008

American Journal of Physiology-Cell Physiology

111

107

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Gene expression of the tight junction protein occludin includes differential splicing and alternative promoter usage

Cited by 59 publications

References 35 publications

The Tight Junction Protein Occludin and the Adherens Junction Protein α-Catenin Share a Common Interaction Mechanism with ZO-1

The Tight Junction Protein Occludin and the Adherens Junction Protein α-Catenin Share a Common Interaction Mechanism with ZO-1

Splicing Diversity of the Human OCLN Gene and Its Biological Significance for Hepatitis C Virus Entry

Proinflammatory cytokines tumor necrosis factor-α and interferon-γ alter tight junction structure and function in the rat parotid gland Par-C10 cell line

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