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. 1996 Sep;70(9):6269–6277. doi: 10.1128/jvi.70.9.6269-6277.1996

Autoantigens interact with cis-acting elements of rubella virus RNA.

G P Pogue 1, J Hofmann 1, R Duncan 1, J M Best 1, J Etherington 1, R D Sontheimer 1, H L Nakhasi 1
PMCID: PMC190652  PMID: 8709254

Abstract

Rubella virus (RV) infections in adult women can be associated with acute and chronic arthritic symptoms. In many autoimmune individuals, antibodies are found targeting endogenous proteins, called autoantigens, contained in ribonucleoprotein complexes (RNPs). In order to understand the molecular mechanisms involved in the RV-associated pathology, we investigated the nature of cellular factors binding RV RNA and whether such RNPs were recognized by antibodies in infected individuals. Previously, we noted that cellular proteins associated with the RV 5'(+) stem-loop (SL) RNA are recognized by serum with Ro reactivity. To better understand the nature of the autoantigens binding RV cis-acting elements, serum samples from individuals with various autoimmune diseases were tested for their ability to immunoprecipitate RNPs containing labeled RV RNAs. A subset of serum samples recognizing autoantigen La, or Ro and La, immunoprecipitated both the RV 5'(+)SL and 3'(+)SL RNA-protein complexes. Autoantigens binding the RV 5'(+)SL and 3'(+)SL RNAs differed in molecular mass, specificities for respective RNA binding substrates, and sensitivity to alkaline phosphatase treatment. The La autoantigen was found to interact with the RV 5'(+)SL RNA as determined by immunological techniques and binding reactions with mixtures containing recombinant La protein. To test whether there is a correlation between La binding to an RV RNA element and the appearance of an anti-La response, we measured anti-La titers in RV-infected individuals. Significant anti-La activity was detected in approximately one-third of RV-infected individuals 2 years postinfection.

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Selected References

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  1. Atreya C. D., Singh N. K., Nakhasi H. L. The rubella virus RNA binding activity of human calreticulin is localized to the N-terminal domain. J Virol. 1995 Jun;69(6):3848–3851. doi: 10.1128/jvi.69.6.3848-3851.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Best J. M., Banatvala J. E., Bowen J. M. New Japanese rubella vaccine: comparative trials. Br Med J. 1974 Jul 27;3(5925):221–224. doi: 10.1136/bmj.3.5925.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Chambers J. C., Kenan D., Martin B. J., Keene J. D. Genomic structure and amino acid sequence domains of the human La autoantigen. J Biol Chem. 1988 Dec 5;263(34):18043–18051. [PubMed] [Google Scholar]
  4. Chang Y. N., Kenan D. J., Keene J. D., Gatignol A., Jeang K. T. Direct interactions between autoantigen La and human immunodeficiency virus leader RNA. J Virol. 1994 Nov;68(11):7008–7020. doi: 10.1128/jvi.68.11.7008-7020.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chantler J. K., Ford D. K., Tingle A. J. Persistent rubella infection and rubella-associated arthritis. Lancet. 1982 Jun 12;1(8285):1323–1325. doi: 10.1016/s0140-6736(82)92398-4. [DOI] [PubMed] [Google Scholar]
  6. Chantler J. K., Ford D. K., Tingle A. J. Rubella-associated arthritis: rescue of rubella virus from peripheral blood lymphocytes two years postvaccination. Infect Immun. 1981 Jun;32(3):1274–1280. doi: 10.1128/iai.32.3.1274-1280.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chantler J. K., Tingle A. J., Petty R. E. Persistent rubella virus infection associated with chronic arthritis in children. N Engl J Med. 1985 Oct 31;313(18):1117–1123. doi: 10.1056/NEJM198510313131803. [DOI] [PubMed] [Google Scholar]
  8. Cooper L. Z., Ziring P. R., Weiss H. J., Matters B. A., Krugman S. Transient arthritis after rubella vaccination. Am J Dis Child. 1969 Aug;118(2):218–225. doi: 10.1001/archpedi.1969.02100040220011. [DOI] [PubMed] [Google Scholar]
  9. Davidson H. W., Watts C. Epitope-directed processing of specific antigen by B lymphocytes. J Cell Biol. 1989 Jul;109(1):85–92. doi: 10.1083/jcb.109.1.85. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dominguez G., Wang C. Y., Frey T. K. Sequence of the genome RNA of rubella virus: evidence for genetic rearrangement during togavirus evolution. Virology. 1990 Jul;177(1):225–238. doi: 10.1016/0042-6822(90)90476-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dong X., Hamilton K. J., Satoh M., Wang J., Reeves W. H. Initiation of autoimmunity to the p53 tumor suppressor protein by complexes of p53 and SV40 large T antigen. J Exp Med. 1994 Apr 1;179(4):1243–1252. doi: 10.1084/jem.179.4.1243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Francoeur A. M., Mathews M. B. Interaction between VA RNA and the lupus antigen La: formation of a ribonucleoprotein particle in vitro. Proc Natl Acad Sci U S A. 1982 Nov;79(22):6772–6776. doi: 10.1073/pnas.79.22.6772. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gottlieb E., Steitz J. A. Function of the mammalian La protein: evidence for its action in transcription termination by RNA polymerase III. EMBO J. 1989 Mar;8(3):851–861. doi: 10.1002/j.1460-2075.1989.tb03446.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Howson C. P., Katz M., Johnston R. B., Jr, Fineberg H. V. Chronic arthritis after rubella vaccination. Clin Infect Dis. 1992 Aug;15(2):307–312. doi: 10.1093/clinids/15.2.307. [DOI] [PubMed] [Google Scholar]
  15. Maraia R. J., Kenan D. J., Keene J. D. Eukaryotic transcription termination factor La mediates transcript release and facilitates reinitiation by RNA polymerase III. Mol Cell Biol. 1994 Mar;14(3):2147–2158. doi: 10.1128/mcb.14.3.2147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. McCauliffe D. P., Lux F. A., Lieu T. S., Sanz I., Hanke J., Newkirk M. M., Bachinski L. L., Itoh Y., Siciliano M. J., Reichlin M. Molecular cloning, expression, and chromosome 19 localization of a human Ro/SS-A autoantigen. J Clin Invest. 1990 May;85(5):1379–1391. doi: 10.1172/JCI114582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Meerovitch K., Svitkin Y. V., Lee H. S., Lejbkowicz F., Kenan D. J., Chan E. K., Agol V. I., Keene J. D., Sonenberg N. La autoantigen enhances and corrects aberrant translation of poliovirus RNA in reticulocyte lysate. J Virol. 1993 Jul;67(7):3798–3807. doi: 10.1128/jvi.67.7.3798-3807.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Miki N. P., Chantler J. K. Differential ability of wild-type and vaccine strains of rubella virus to replicate and persist in human joint tissue. Clin Exp Rheumatol. 1992 Jan-Feb;10(1):3–12. [PubMed] [Google Scholar]
  19. Nakhasi H. L., Rouault T. A., Haile D. J., Liu T. Y., Klausner R. D. Specific high-affinity binding of host cell proteins to the 3' region of rubella virus RNA. New Biol. 1990 Mar;2(3):255–264. [PubMed] [Google Scholar]
  20. Nakhasi H. L., Singh N. K., Pogue G. P., Cao X. Q., Rouault T. A. Identification and characterization of host factor interactions with cis-acting elements of rubella virus RNA. Arch Virol Suppl. 1994;9:255–267. doi: 10.1007/978-3-7091-9326-6_26. [DOI] [PubMed] [Google Scholar]
  21. Nakhasi H. L., Zheng D. X., Hewlett I. K., Liu T. Y. Rubella virus replication: effect of interferons and actinomycin D. Virus Res. 1988 Apr;10(1):1–15. doi: 10.1016/0168-1702(88)90053-6. [DOI] [PubMed] [Google Scholar]
  22. Nash P. D., Opas M., Michalak M. Calreticulin: not just another calcium-binding protein. Mol Cell Biochem. 1994 Jun 15;135(1):71–78. doi: 10.1007/BF00925962. [DOI] [PubMed] [Google Scholar]
  23. Ogra P. L., Chiba Y., Ogra S. S., Dzierba J. L., Herd J. K. Rubella-virus infection in juvenile rheumatoid arthritis. Lancet. 1975 May 24;1(7917):1157–1161. doi: 10.1016/s0140-6736(75)93136-0. [DOI] [PubMed] [Google Scholar]
  24. Phillips P. E. Viruses and systemic lupus erythematosus. Bull Rheum Dis. 1977;28(7):954–959. [PubMed] [Google Scholar]
  25. Pogue G. P., Cao X. Q., Singh N. K., Nakhasi H. L. 5' sequences of rubella virus RNA stimulate translation of chimeric RNAs and specifically interact with two host-encoded proteins. J Virol. 1993 Dec;67(12):7106–7117. doi: 10.1128/jvi.67.12.7106-7117.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Polk B. F., Modlin J. F., White J. A., DeGirolami P. C. A controlled comparison of joint reactions among women receiving one of two rubella vaccines. Am J Epidemiol. 1982 Jan;115(1):19–25. doi: 10.1093/oxfordjournals.aje.a113276. [DOI] [PubMed] [Google Scholar]
  27. Rinke J., Steitz J. A. Precursor molecules of both human 5S ribosomal RNA and transfer RNAs are bound by a cellular protein reactive with anti-La lupus antibodies. Cell. 1982 May;29(1):149–159. doi: 10.1016/0092-8674(82)90099-x. [DOI] [PubMed] [Google Scholar]
  28. Rokeach L. A., Haselby J. A., Meilof J. F., Smeenk R. J., Unnasch T. R., Greene B. M., Hoch S. O. Characterization of the autoantigen calreticulin. J Immunol. 1991 Nov 1;147(9):3031–3039. [PubMed] [Google Scholar]
  29. Rosa M. D., Gottlieb E., Lerner M. R., Steitz J. A. Striking similarities are exhibited by two small Epstein-Barr virus-encoded ribonucleic acids and the adenovirus-associated ribonucleic acids VAI and VAII. Mol Cell Biol. 1981 Sep;1(9):785–796. doi: 10.1128/mcb.1.9.785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rosen A., Casciola-Rosen L., Ahearn J. Novel packages of viral and self-antigens are generated during apoptosis. J Exp Med. 1995 Apr 1;181(4):1557–1561. doi: 10.1084/jem.181.4.1557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Singh N. K., Atreya C. D., Nakhasi H. L. Identification of calreticulin as a rubella virus RNA binding protein. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12770–12774. doi: 10.1073/pnas.91.26.12770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Slater P. E., Ben-Zvi T., Fogel A., Ehrenfeld M., Ever-Hadani S. Absence of an association between rubella vaccination and arthritis in underimmune postpartum women. Vaccine. 1995 Nov;13(16):1529–1532. doi: 10.1016/0264-410x(95)00096-j. [DOI] [PubMed] [Google Scholar]
  33. Spruance S. L., Smith C. B. Joint complications associated with derivatives of HPV-77 rubella virus vaccine. Am J Dis Child. 1971 Aug;122(2):105–111. doi: 10.1001/archpedi.1971.02110020039002. [DOI] [PubMed] [Google Scholar]
  34. St Clair E. W., Kenan D., Burch J. A., Jr, Keene J. D., Pisetsky D. S. The fine specificity of anti-La antibodies induced in mice by immunization with recombinant human La autoantigen. J Immunol. 1990 May 15;144(10):3868–3876. [PubMed] [Google Scholar]
  35. Stefano J. E. Purified lupus antigen La recognizes an oligouridylate stretch common to the 3' termini of RNA polymerase III transcripts. Cell. 1984 Jan;36(1):145–154. doi: 10.1016/0092-8674(84)90083-7. [DOI] [PubMed] [Google Scholar]
  36. Svitkin Y. V., Pause A., Sonenberg N. La autoantigen alleviates translational repression by the 5' leader sequence of the human immunodeficiency virus type 1 mRNA. J Virol. 1994 Nov;68(11):7001–7007. doi: 10.1128/jvi.68.11.7001-7007.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Tan E. M. Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology. Adv Immunol. 1989;44:93–151. doi: 10.1016/s0065-2776(08)60641-0. [DOI] [PubMed] [Google Scholar]
  38. Tan E. M. Autoimmunity and apoptosis. J Exp Med. 1994 Apr 1;179(4):1083–1086. doi: 10.1084/jem.179.4.1083. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Thompson G. R., Ferreyra A., Brackett R. G. Acute arthritis complicating rubella vaccination. Arthritis Rheum. 1971 Jan-Feb;14(1):19–26. doi: 10.1002/art.1780140104. [DOI] [PubMed] [Google Scholar]
  40. Tingle A. J., Allen M., Petty R. E., Kettyls G. D., Chantler J. K. Rubella-associated arthritis. I. Comparative study of joint manifestations associated with natural rubella infection and RA 27/3 rubella immunisation. Ann Rheum Dis. 1986 Feb;45(2):110–114. doi: 10.1136/ard.45.2.110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tingle A. J., Chantler J. K., Pot K. H., Paty D. W., Ford D. K. Postpartum rubella immunization: association with development of prolonged arthritis, neurological sequelae, and chronic rubella viremia. J Infect Dis. 1985 Sep;152(3):606–612. doi: 10.1093/infdis/152.3.606. [DOI] [PubMed] [Google Scholar]
  42. Wilusz J., Kurilla M. G., Keene J. D. A host protein (La) binds to a unique species of minus-sense leader RNA during replication of vesicular stomatitis virus. Proc Natl Acad Sci U S A. 1983 Oct;80(19):5827–5831. doi: 10.1073/pnas.80.19.5827. [DOI] [PMC free article] [PubMed] [Google Scholar]

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