Advertisement

Virus Genes

, Volume 16, Issue 2, pp 177–183 | Cite as

The Rubella Virus Putative Replicase Interacts with the Retinoblastoma Tumor Suppressor Protein

  • Chintamani D. Atreya
  • Nancy S. Lee
  • Ren-Yo Forng
  • Jorg Hofmann
  • Glennelle Washington
  • Gerald Marti
  • Hira L. Nakhasi
Article

Abstract

In utero fetal infection of rubella virus (RV), a positive-stranded RNA virus, frequently induces birth defects if contracted in the first trimester of pregnancy. The underlying mechanism of RV-induced birth defects is not known. Birth defects are also common in certain DNA viral infections such as human cytomegalovirus (HCMV). During HCMV infection, one of its proteins interacts with a cell growth regulatory protein, the retinoblastoma protein (Rb) and stimulates DNA synthesis which is associated with chromosomal damage and cellular mitotic arrest. These affects have been implicated in HCMV induced teratogenesis. Since RV and HCMV both cause teratogenesis, we postulated that during RV infection, a virus-encoded protein might interact with Rb and affect fetal cell growth. In the present study, we have identified a known Rb-binding motif, L×C×E (LPCAE) in the carboxy-terminal half of the putative replicase (NSP90) of RV and demonstrated that the C-terminal region specifically binds to GST-Rb in vitro. Further, by coimmunoprecipitating NSP90 and Rb using specific antibodies to respective proteins, we have confirmed that NSP90 specifically binds to Rb in vivo as well. In addition, RV replication was shown to be less in null-mutant (Rb−/−) mouse embryonic fibroblast cells than in wild-type (Rb+/+) cells, suggesting a possible physiological role for this interaction. Thus, in facilitating RV replication, binding of NSP90 to Rb potentially alters the cell growth regulatory property of Rb, and this could be one of the initial steps in RV-induced teratogenesis.

retinoblastoma protein rubella virus NSP90 replication teratogenesis 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Frey T.K., Advances in Virus Res 44, 64–159, 1994.Google Scholar
  2. 2.
    Gregg N.M., Trans Ophthalmol Soc Aust 3, 35–46, 1941.Google Scholar
  3. 3.
    Munro N.D., Sheppard S., Smithells R.W., Holzel H., and Jones G., Lancet 2, 201–204, 1987.PubMedCrossRefGoogle Scholar
  4. 4.
    Ray C.G., in Braunwald E., Isselbacher K.J., and Petersdorf R.G. (eds). Principles of Internal Medicine. McGraw-Hill, New York, 1987, pp. 684–686.Google Scholar
  5. 5.
    Jault F.M., Jault J-M., Ruchti Fortunato E.A., Clark C., Corbeil J., Richman D.D., and Spector D.H., J Virol 69, 6697–6704, 1995.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Kamiya S., Tanaka J., Ogura T., Ogura H., Sato H., and Hatano M. Arch Virol, 89, 131–144, 1986.PubMedCrossRefGoogle Scholar
  7. 7.
    Fortunato E.A., Sommer H.M., Yoder K., and Spector D.H., J Virol 71, 8176–8185, 1997.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Taya Y., TIBS, 22, 14–17, 1997.PubMedGoogle Scholar
  9. 9.
    White R., TIBS, 22, 77–80, 1997.PubMedGoogle Scholar
  10. 10.
    Wang J.Y.J., Knudsen E.S., and Welch P., Advances in Cancer Res 54, 26–85, 1994.Google Scholar
  11. 11.
    Plotkin S.A. and Vaheri A., Science, 156, 659–661, 1967.PubMedCrossRefGoogle Scholar
  12. 12.
    Nakhasi H.L., Rouault T.A., Haile D.J., Liu T-Y., and Klausner R.D., New Biol 2, 255–264, 1990.PubMedGoogle Scholar
  13. 13.
    Chen P-L., Riley D.J., and Lee W-H., Genes & Dev 10, 2794–2804, 1996.CrossRefGoogle Scholar
  14. 14.
    Dominguez G., Wang C-Y., and Frey T.K., Virology, 177, 225–238, 1990.PubMedCrossRefGoogle Scholar
  15. 15.
    Durfee T., Becherer K., Chen P-L., Yeh S-H., Yang Y., Kilbum A., Lee W-H., and Elledge S.J., Genes & Dev 7, 555–569, 1993.CrossRefGoogle Scholar
  16. 16.
    Singh N.K., Atreya C.D., and Nakhasi H.L., Proc Natl Acad Sci USA 91, 12770–12774, 1994.PubMedCrossRefGoogle Scholar
  17. 17.
    Forng Y.T, and Frey T.K., Virology, 206, 843–853, 1995.PubMedCrossRefGoogle Scholar
  18. 18.
    Atreya C.D. and Pirone T.P., Proc Natl Acad Sci USA, 90, 11919–11923, 1993.PubMedCrossRefGoogle Scholar
  19. 19.
    Ponte P., Ng S-Y., Engel J., Gunning P., and Kedes L., Nucleic acid Res 12, 1687-, 1984PubMedCrossRefGoogle Scholar
  20. 20.
    Gillam S. (Genbank Accession No. X72393).Google Scholar
  21. 21.
    Johnstone P. Cloning and sequence analysis of rubella virus nonstructural protein coding region. Ph. D. Thesis, University of Surrey, UK, 1994.Google Scholar
  22. 22.
    Pugachev K.V., Abemathy E.S., and Frey T.K., Arch Virol 141, 1165–1180, 1997.CrossRefGoogle Scholar
  23. 23.
    Lamb R.A. and Krug R. in Fields B.N., Knipe D.M., and Howley P.M. (eds). Field's Virology. Lippincott-Raven publishers, New York, pp. 1353–1396.Google Scholar

Copyright information

© Kluwer Academic Publishers 1998

Authors and Affiliations

  • Chintamani D. Atreya
    • 1
  • Nancy S. Lee
    • 2
  • Ren-Yo Forng
    • 1
  • Jorg Hofmann
    • 3
  • Glennelle Washington
    • 4
  • Gerald Marti
    • 4
  • Hira L. Nakhasi
    • 2
  1. 1.Division of Viral ProductsGermany
  2. 2.Division of Allergenic Products and ParasitologyGermany
  3. 3.Institut fur VirologieUniversity of LeipzigGermany
  4. 4.Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug AdministrationBethesda

Personalised recommendations