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J. Biol. Chem., Vol. 283, Issue 13, 8643-8653, March 28, 2008

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Correlation of the Tight Junction-like Distribution of Claudin-1 to the Cellular Tropism of Hepatitis C Virus^*

Wei Yang, Chao Qiu¹, Nabanita Biswas, Jing Jin, Simon C. Watkins^¶, Ronald C. Montelaro, Carolyn B. Coyne^¶, and Tianyi Wang²

From the Departments of Infectious Diseases and Microbiology, Microbiology and Molecular Genetics, and ^¶Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261

Claudin-1 (CLDN1), a tight junction (TJ) protein, has recently been identified as an entry co-receptor for hepatitis C virus (HCV). Ectopic expression of CLDN1 rendered several non-hepatic cell lines permissive to HCV infection. However, little is known about the mechanism by which CLDN1 mediates HCV entry. It is believed that an additional entry receptor(s) is required because ectopic expression of CLDN1 in both HeLa and NIH3T3 cells failed to confer susceptibility to viral infection. Here we found that CLDN1 was co-immunoprecipitated with both HCV envelope proteins when expressed in 293T cells. Results from biomolecular fluorescence complementation assay showed that overexpressed CLDN1 also formed complexes with CD81 and low density lipoprotein receptor. Subsequent imaging analysis revealed that CLDN1 was highly enriched at sites of cell-cell contact in permissive cell lines, co-localizing with the TJ marker, ZO-1. However, in both HeLa and NIH3T3 cells the ectopically expressed CLDN1 appeared to reside predominantly in intracellular vesicles. The CLDN1-CD81 complex formed in HeLa cells was also exclusively distributed intracellularly, co-localizing with EEA1, an early endosomal marker. Correspondingly, transepithelial electric resistance, obtained from the naturally susceptible human liver cell line, Huh7, was much higher than that of the HeLa-CLDN1 cell line, suggesting that Huh7 is likely to form functional tight junctions. Finally, the disruption of TJ-enriched CLDN1 by tumor necrosis factor- treatment markedly reduced the susceptibility of Huh7.5.1 cells to HCV infection. Our results suggest that the specific localization pattern of CLDN1 may be crucial in the regulation of HCV cellular tropism.

Received for publication, December 3, 2007 , and in revised form, January 22, 2008.

^* This work was supported in part by National Institutes of Health Grant 1R21AI068784-01A1 (to T. W.) and University of Pittsburgh Central Research Development Funds (to T. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

¹ Present address: Laboratoire d'Immunologie, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CR-CHUM) Saint-Luc, 264 Rene Levesque Est, Montréal, Québec H2X1P1, Canada.

² To whom correspondence should be addressed: Dept. of Infectious Diseases and Microbiology, Graduate School of Public Health, 130 DeSoto St., Pittsburgh, PA 15261. Tel.: 412-383-9916; Fax: 412-383-8926; E-mail: tywang{at}pitt.edu.

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