title: Splicing diversity of the human OCLN gene and its biological significance for hepatitis C virus entry.
abstract: 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, OCLN-ex3pdel, 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.
authors.affiliation: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health, 8717 Grovemont Circle, Bethesda, MD 20892-4605, USA.
authors.forename: Indu
authors.initials: I
authors.lastname: Kohaar
authors.forename: Alexander
authors.initials: A
authors.lastname: Ploss
authors.forename: Evgenia
authors.initials: E
authors.lastname: Korol
authors.forename: Kathy
authors.initials: K
authors.lastname: Mu
authors.forename: John W
authors.initials: JW
authors.lastname: Schoggins
authors.forename: Thomas R
authors.initials: TR
authors.lastname: O'Brien
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.forename: Ludmila
authors.initials: L
authors.lastname: Prokunina-Olsson
mesh_terms: D017398:Alternative Splicing; D002884:Chromosomes, Human, Pair 15; D005091:Exons; D006367:HeLa Cells; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000150:complications / Q000503:physiopathology; D006801:Humans; D008099:Liver / Q000502:physiology / Q000821:virology; D008113:Liver Neoplasms / Q000209:etiology / Q000821:virology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D062793:Occludin; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution; D053586:Virus Internalization
chemical_list: D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D020033:Protein Isoforms
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