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

Journal of Virology, July 2010, p. 6987-6994, Vol. 84, No. 14


0022-538X/10/$012.00+0 doi:10.1128/JVI.00196-10

Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Indu Kohaar,1 Alexander Ploss,2 Evgenia Korol,2 Kathy Mu,2 John W. Schoggins,2 Thomas R. O'Brien,3 Charles M. Rice,2 and Ludmila Prokunina-Olsson1*

Laboratory of Translational Genomics,1 Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892,3 Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Diseases, The Rockefeller University, 1230 York Avenue, Box 64, New York, New York 100652

Received 27 January 2010/ Accepted 29 April 2010

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.

* Corresponding author. Mailing address: Laboratory of Translational Genomics, National Cancer Institute, National Institutes of Health, 8717 Grovemont Circle, Bethesda, MD 20892-4605. Phone: (301) 443-5297. Fax: (301) 443-3234. E-mail: prokuninal@mail.nih.gov


Published ahead of print on 12 May 2010.

Supplemental material for this article may be found at http://jvi.asm.org/ .

Journal of Virology, July 2010, p. 6987-6994, Vol. 84, No. 14

0022-538X/10/$012.00+0 doi:10.1128/JVI.00196-10

Copyright © 2010, American Society for Microbiology. All Rights Reserved
 
http://jvi.asm.org/cgi/content/abstract/84/14/6987?view=short&fp=6987&vol=84&lookupType=volpage