1887

Abstract

The RNA-dependent RNA polymerase (NS5B) of hepatitis C virus (HCV) is part of the viral replicative complex and plays a crucial role in HCV replication. It has been described that NS5B interacts with cellular proteins, and that interactions between NS5B and host proteins are crucial for viral replication. Some of the host factors involved in the HCV replication cycle include the oestrogen receptor alpha (ESR1), protein kinases (c-Src) and chaperones (Hsp70). In this report, we determine the requirements for the interplay between NS5B and the domain C of ESR1 (ESR1C) by using Förster Resonance Energy Transfer. NS5B–ESR1C and ESR1C–ESR1C interactions are dependent on ionic strength, indicating that contacts are mainly electrostatic. Additionally, NS5B residues involved in NS5B oligomerization were also essential for NS5B–ESR1C interaction. The study of the interactions among viral and host factors will provide data to establish innovative therapeutic strategies and the development of new antiviral drugs.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.039396-0
2012-04-01
2019-10-16
Loading full text...

Full text loading...

/deliver/fulltext/jgv/93/4/780.html?itemId=/content/journal/jgv/10.1099/vir.0.039396-0&mimeType=html&fmt=ahah

References

  1. Behrens S. E., Tomei L., De Francesco R.. ( 1996;). Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus. . EMBO J 15:, 12–22.[PubMed]
    [Google Scholar]
  2. Bellón-Echeverría I., López-Jiménez A. J., Clemente-Casares P., Mas A.. ( 2010;). Monitoring hepatitis C virus (HCV) RNA-dependent RNA polymerase oligomerization by a FRET-based in vitro system. . Antiviral Res 87:, 57–66. [CrossRef][PubMed]
    [Google Scholar]
  3. Chinnaswamy S., Yarbrough I., Palaninathan S., Kumar C. T., Vijayaraghavan V., Demeler B., Lemon S. M., Sacchettini J. C., Kao C. C.. ( 2008;). A locking mechanism regulates RNA synthesis and host protein interaction by the hepatitis C virus polymerase. . J Biol Chem 283:, 20535–20546. [CrossRef][PubMed]
    [Google Scholar]
  4. Chinnaswamy S., Murali A., Li P., Fujisaki K., Kao C. C.. ( 2010;). Regulation of de novo-initiated RNA synthesis in hepatitis C virus RNA-dependent RNA polymerase by intermolecular interactions. . J Virol 84:, 5923–5935. [CrossRef][PubMed]
    [Google Scholar]
  5. Clemente-Casares P., López-Jiménez A. J., Bellón-Echeverría I., Encinar J. A., Martínez-Alfaro E., Pérez-Flores R., Mas A.. ( 2011;). De novo polymerase activity and oligomerization of hepatitis C virus RNA-dependent RNA-polymerases from genotypes 1 to 5. . PLoS ONE 6:, e18515. [CrossRef][PubMed]
    [Google Scholar]
  6. Flisiak R., Feinman S. V., Jablkowski M., Horban A., Kryczka W., Pawlowska M., Heathcote J. E., Mazzella G., Vandelli C.. & other authors ( 2009;). The cyclophilin inhibitor Debio 025 combined with PEG IFNα2a significantly reduces viral load in treatment-naïve hepatitis C patients. . Hepatology 49:, 1460–1468. [CrossRef][PubMed]
    [Google Scholar]
  7. Gastaminza P., Whitten-Bauer C., Chisari F. V.. ( 2010;). Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection. . Proc Natl Acad Sci U S A 107:, 291–296. [CrossRef][PubMed]
    [Google Scholar]
  8. Georgel P., Schuster C., Zeisel M. B., Stoll-Keller F., Berg T., Bahram S., Baumert T. F.. ( 2010;). Virus-host interactions in hepatitis C virus infection: implications for molecular pathogenesis and antiviral strategies. . Trends Mol Med 16:, 277–286. [CrossRef][PubMed]
    [Google Scholar]
  9. Gerold G., Rice C. M.. ( 2011;). Locking out hepatitis C. . Nat Med 17:, 542–544. [CrossRef][PubMed]
    [Google Scholar]
  10. Guedj J., Rong L., Dahari H., Perelson A. S.. ( 2010;). A perspective on modelling hepatitis C virus infection. . J Viral Hepat 17:, 825–833. [CrossRef][PubMed]
    [Google Scholar]
  11. Hayashida K., Shoji I., Deng L., Jiang D. P., Ide Y. H., Hotta H.. ( 2010;). 17β-estradiol inhibits the production of infectious particles of hepatitis C virus. . Microbiol Immunol 54:, 684–690. [CrossRef][PubMed]
    [Google Scholar]
  12. Khattab M. A.. ( 2009;). Targeting host factors: a novel rationale for the management of hepatitis C virus. . World J Gastroenterol 15:, 3472–3479. [CrossRef][PubMed]
    [Google Scholar]
  13. Lohmann V., Körner F., Herian U., Bartenschlager R.. ( 1997;). Biochemical properties of hepatitis C virus NS5B RNA-dependent RNA polymerase and identification of amino acid sequence motifs essential for enzymatic activity. . J Virol 71:, 8416–8428.[PubMed]
    [Google Scholar]
  14. Mangelsdorf D. J., Thummel C., Beato M., Herrlich P., Schütz G., Umesono K., Blumberg B., Kastner P., Mark M.. & other authors ( 1995;). The nuclear receptor superfamily: the second decade. . Cell 83:, 835–839. [CrossRef][PubMed]
    [Google Scholar]
  15. Nagy P. D., Wang R. Y., Pogany J., Hafren A., Makinen K.. ( 2011;). Emerging picture of host chaperone and cyclophilin roles in RNA virus replication. . Virology 411:, 374–382. [CrossRef][PubMed]
    [Google Scholar]
  16. Paeshuyse J., Kaul A., De Clercq E., Rosenwirth B., Dumont J. M., Scalfaro P., Bartenschlager R., Neyts J.. ( 2006;). The non-immunosuppressive cyclosporin DEBIO-025 is a potent inhibitor of hepatitis C virus replication in vitro. . Hepatology 43:, 761–770. [CrossRef][PubMed]
    [Google Scholar]
  17. Qin W., Luo H., Nomura T., Hayashi N., Yamashita T., Murakami S.. ( 2002;). Oligomeric interaction of hepatitis C virus NS5B is critical for catalytic activity of RNA-dependent RNA polymerase. . J Biol Chem 277:, 2132–2137. [CrossRef][PubMed]
    [Google Scholar]
  18. Ranjith-Kumar C. T., Kim Y. C., Gutshall L., Silverman C., Khandekar S., Sarisky R. T., Kao C. C.. ( 2002;). Mechanism of de novo initiation by the hepatitis C virus RNA-dependent RNA polymerase: role of divalent metals. . J Virol 76:, 12513–12525. [CrossRef][PubMed]
    [Google Scholar]
  19. Suzuki T.. ( 2010;). A hepatitis C virus-host interaction involved in viral replication: toward the identification of antiviral targets. . Jpn J Infect Dis 63:, 307–311.[PubMed]
    [Google Scholar]
  20. Vidalain P. O., Tangy F.. ( 2010;). Virus-host protein interactions in RNA viruses. . Microbes Infect 12:, 1134–1143. [CrossRef][PubMed]
    [Google Scholar]
  21. Watashi K., Ishii N., Hijikata M., Inoue D., Murata T., Miyanari Y., Shimotohno K.. ( 2005;). Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. . Mol Cell 19:, 111–122. [CrossRef][PubMed]
    [Google Scholar]
  22. Watashi K., Inoue D., Hijikata M., Goto K., Aly H. H., Shimotohno K.. ( 2007;). Anti-hepatitis C virus activity of tamoxifen reveals the functional association of estrogen receptor with viral RNA polymerase NS5B. . J Biol Chem 282:, 32765–32772. [CrossRef][PubMed]
    [Google Scholar]
  23. Winkler C. A.. ( 2008;). Identifying host targets for drug development with knowledge from genome-wide studies: lessons from HIV-AIDS. . Cell Host Microbe 3:, 203–205. [CrossRef][PubMed]
    [Google Scholar]
  24. Zacharias D. A., Violin J. D., Newton A. C., Tsien R. Y.. ( 2002;). Partitioning of lipid-modified monomeric GFPs into membrane microdomains of live cells. . Science 296:, 913–916. [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.039396-0
Loading
/content/journal/jgv/10.1099/vir.0.039396-0
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error