Structure of the Conserved Cytoplasmic C-terminal Domain of Occludin: Identification of the ZO-1 Binding Surface

Li, Yuanhe; Fanning, Alan S.; Anderson, James M.; Lavie, A.

doi:10.1016/j.jmb.2005.07.017

Cited by 112 publications

(161 citation statements)

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“…The animals did not exhibit any clear phenotypes except chronic gastritis, abnormalities in the testes, salivary glands, and bones, and progressive accumulation of mineral deposits in the brains of aged animals (2). The resulting OCLN-ex3del protein is N-terminally truncated and lacks the extracellular MARVEL domain but retains the intracellular ELL domain (7). In agreement with the reported absence of expression of this form at the TJ (2), we did not observe expression of the human recombinant protein encoded by this form on the cell membrane.…”

Section: Discussionsupporting

confidence: 90%

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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Section: Discussionsupporting

confidence: 90%

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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“…ZO-1 is the key accessory protein of the TJ which links each of these transmembrane proteins at their C-termini to the actin cytoskeleton (Farshori and Kachar, 1999;Mitic et al, 2000). In addition, ZO-1 has an apparent role in the organization and formation of the TJ by recruiting and trafficking transmembrane proteins to the TJ microdomain (Li et al, 2005;Sheth et al, 1997;Umeda et al, 2004). We hypothesize that the increased co-localization of claudin-5 and ZO-1 decreases the interactions of both occludin and JAM-1 with this support protein.…”

Section: Discussionmentioning

confidence: 99%

Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain

et al. 2006

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The blood-brain barrier (BBB) is a dynamic system which maintains brain homeostasis and limits CNS penetration via interactions of transmembrane and intracellular proteins. Inflammatory pain (IP) is a condition underlying several diseases with known BBB perturbations, including stroke, Parkinson's, multiple sclerosis and Alzheimer's. Exploring the underlying pathology of chronic IP, we demonstrated alterations in BBB paracellular permeability with correlating changes in tight junction (TJ) proteins: occludin and claudin-5. The present study examines the IP-induced molecular changes leading to a loss in functional BBB integrity. IP was induced by injection of Complete Freund's Adjuvant (CFA) into the plantar surface of the right hindpaw of female Sprague-Dawley rats. Inflammation and hyperalgesia were confirmed, and BBB paracellular permeability was assessed by in situ brain perfusion of [ 14 C]sucrose (paracellular diffusion marker). The permeability of the BBB was significantly increased at 24 and 72 h post-CFA. Analysis of the TJ proteins, which control the paracellular pathway, demonstrated decreased claudin-5 expression at 24 h, and an increase at 48 and 72 h post-injection. Occludin expression was significantly decreased 72 h post-CFA. Expression of junction adhesion molecule-1 (JAM-1) increased 48 h and decreased by 72 h post-CFA. Confocal microscopy demonstrated continuous expression of both occludin and JAM-1, each co-localizing with ZO-1. The increased claudin-5 expression was not limited to the junction. These results provide evidence that chronic IP causes dramatic alterations in specific cytoarchitectural proteins and demonstrate alterations in molecular properties during CFA, resulting in significant changes in BBB paracellular permeability.

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“…8C,D). In contrast, expression of EGFP-occludin ΔOCEL , which cannot bind to ZO-1 (Li et al, 2005), increased single-lumen formation minimally (16%±1%). The ZO-1-binding OCEL domain of occludin is therefore necessary for single-lumen formation.…”

Section: Full-length But Not Zo-1-binding Defective Occludin Restormentioning

confidence: 92%

ZO-1 interactions with F-actin and occludin direct epithelial polarization and single lumen specification in 3D culture

Odenwald

Choi

Buckley

et al. 2016

Journal of Cell Science

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103

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Epithelia within tubular organs form and expand lumens. Failure of these processes can result in serious developmental anomalies. Although tight junction assembly is crucial to epithelial polarization, the contribution of specific tight junction proteins to lumenogenesis is undefined. Here, we show that ZO-1 (also known as TJP1) is necessary for the formation of single lumens. Epithelia lacking this tight junction scaffolding protein form cysts with multiple lumens and are defective in the earliest phases of polarization, both in two and three dimensions. Expression of ZO-1 domain-deletion mutants demonstrated that the actin-binding region and U5-GuK domain are crucial to single lumen development. For actin-binding region, but not U5-GuK domain, mutants, this could be overcome by strong polarization cues from the extracellular matrix. Analysis of the U5-GuK binding partners shroom2, α-catenin and occludin showed that only occludin deletion led to multi-lumen cysts. Like ZO-1-deficiency, occludin deletion led to mitotic spindle orientation defects. Single lumen formation required the occludin OCEL domain, which binds to ZO-1. We conclude that ZO-1-occludin interactions regulate multiple phases of epithelial polarization by providing cell-intrinsic signals that are required for single lumen formation.

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Structure of the Conserved Cytoplasmic C-terminal Domain of Occludin: Identification of the ZO-1 Binding Surface

Cited by 112 publications

References 50 publications

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

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

Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain

ZO-1 interactions with F-actin and occludin direct epithelial polarization and single lumen specification in 3D culture

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