1887

Abstract

The leader (L) proteins encoded by picornaviruses of the genus [Theiler's murine encephalomyelitis virus (TMEV) and (EMCV)] are small proteins thought to exert important functions in virus–host interactions. The L protein of persistent TMEV strains was shown to be dispensable for virus replication , but crucial for long-term persistence of the virus in the central nervous system of the mouse. The phenotype of chimeric viruses generated by exchanging the L-coding regions was analysed and it was shown that the L proteins of neurovirulent and persistent TMEV strains are functionally interchangeable and , despite the fact that L is the second most divergent protein encoded by these viruses after the L* protein. The L protein encoded by EMCV and Mengo virus (an EMCV strain) shares about 35 % amino acid identity with that of TMEV. It differs from the latter by lacking a serine/threonine-rich C-terminal domain and by carrying phosphorylated residues not conserved in the TMEV L protein. Our data show that, in spite of these differences, the L protein of Mengo virus shares, with that of TMEV, the ability to inhibit the transcription of type I interferon, cytokine and chemokine genes and to interfere with nucleocytoplasmic trafficking of host-cell proteins. Interestingly, analysis of viral RNA replication of the recombinant viruses raised the hypothesis that L proteins of TMEV and EMCV diverged during evolution to adapt to the different replication fitness of these viruses.

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2006-05-01
2024-03-19
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References

  1. Agol V. I. 2002; Picornavirus genome: an overview. In Molecular Biology of Picornaviruses pp  127–148 Edited by Semler B. L., Wimmer E. Washington, DC: American Society for Microbiology;
    [Google Scholar]
  2. Badshah C., Calenoff M. A., Rundell K. 2000; The leader polypeptide of Theiler's murine encephalomyelitis virus is required for the assembly of virions in mouse L cells. J Virol 74:875–882 [CrossRef]
    [Google Scholar]
  3. Brahic M., Bureau J.-F., Michiels T. 2005; The genetics of the persistent infection and demyelinating disease caused by Theiler's virus. Annu Rev Microbiol 59:279–298 [CrossRef]
    [Google Scholar]
  4. Calenoff M. A., Faaberg K. S., Lipton H. L. 1990; Genomic regions of neurovirulence and attenuation in Theiler murine encephalomyelitis virus. Proc Natl Acad Sci U S A 87:978–982 [CrossRef]
    [Google Scholar]
  5. Calenoff M. A., Badshah C. S., Dal Canto M. C., Lipton H. L., Rundell M. K. 1995; The leader polypeptide of Theiler's virus is essential for neurovirulence but not for virus growth in BHK cells. J Virol 69:5544–5549
    [Google Scholar]
  6. Chen H.-H., Kong W.-P., Roos R. P. 1995; The leader peptide of Theiler's murine encephalomyelitis virus is a zinc-binding protein. J Virol 69:8076–8078
    [Google Scholar]
  7. Chomczynski P., Sacchi N. 1987; Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159
    [Google Scholar]
  8. Delhaye S., van Pesch V., Michiels T. 2004; The leader protein of Theiler's virus interferes with nucleocytoplasmic trafficking of cellular proteins. J Virol 78:4357–4362 [CrossRef]
    [Google Scholar]
  9. Devaney M. A., Vakharia V. N., Lloyd R. E., Ehrenfeld E., Grubman M. J. 1988; Leader protein of foot-and-mouth disease virus is required for cleavage of the p220 component of the cap-binding protein complex. J Virol 62:4407–4409
    [Google Scholar]
  10. Duke G. M., Osorio J. E., Palmenberg A. C. 1990; Attenuation of Mengo virus through genetic engineering of the 5′ noncoding poly(C) tract. Nature 343:474–476 [CrossRef]
    [Google Scholar]
  11. Duke G. M., Hoffman M. A., Palmenberg A. C. 1992; Sequence and structural elements that contribute to efficient encephalomyocarditis virus RNA translation. J Virol 66:1602–1609
    [Google Scholar]
  12. Dvorak C. M. T., Hall D. J., Hill M., Riddle M., Pranter A., Dillman J., Deibel M., Palmenberg A. C. 2001; Leader protein of encephalomyocarditis virus binds zinc, is phosphorylated during viral infection, and affects the efficiency of genome translation. Virology 290:261–271 [CrossRef]
    [Google Scholar]
  13. Fu J., Stein S., Rosenstein L., Bodwell T., Routbort M., Semler B. L., Roos R. P. 1990; Neurovirulence determinants of genetically engineered Theiler viruses. Proc Natl Acad Sci U S A 87:4125–4129 [CrossRef]
    [Google Scholar]
  14. Ghadge G. D., Ma L., Sato S., Kim J., Roos R. P. 1998; A protein critical for a Theiler's virus-induced immune system-mediated demyelinating disease has a cell type-specific antiapoptotic effect and a key role in virus persistence. J Virol 72:8605–8612
    [Google Scholar]
  15. Hoffman M. A., Palmenberg A. C. 1996; Revertant analysis of J-K mutations in the encephalomyocarditis virus internal ribosomal entry site detects an altered leader protein. J Virol 70:6425–6430
    [Google Scholar]
  16. Imai Y., Matsushima Y., Sugimura T., Terada M. 1991; A simple and rapid method for generating a deletion by PCR. Nucleic Acids Res 19:2785 [CrossRef]
    [Google Scholar]
  17. Jnaoui K., Michiels T. 1998; Adaptation of Theiler's virus to L929 cells: mutations in the putative receptor binding site on the capsid map to neutralization sites and modulate viral persistence. Virology 244:397–404 [CrossRef]
    [Google Scholar]
  18. Kaminski A., Hunt S. L., Patton J. G., Jackson R. J. 1995; Direct evidence that polypyrimidine tract binding protein (PTB) is essential for internal initiation of translation of encephalomyocarditis virus RNA. RNA 1:924–938
    [Google Scholar]
  19. Kong W.-P., Roos R. P. 1991; Alternative translation initiation site in the DA strain of Theiler's murine encephalomyelitis virus. J Virol 65:3395–3399
    [Google Scholar]
  20. Kong W.-P., Ghadge G. D., Roos R. P. 1994; Involvement of cardiovirus leader in host cell-restricted virus expression. Proc Natl Acad Sci U S A 91:1796–1800 [CrossRef]
    [Google Scholar]
  21. Kunkel T. A. 1985; Rapid and efficient site-specific mutagenesis without phenotypic selection. Proc Natl Acad Sci U S A 82:488–492 [CrossRef]
    [Google Scholar]
  22. Lipton H. L. 1975; Theiler's virus infection in mice: an unusual biphasic disease process leading to demyelination. Infect Immun 11:1147–1155
    [Google Scholar]
  23. McAllister A., Tangy F., Aubert C., Brahic M. 1989; Molecular cloning of the complete genome of Theiler's virus, strain DA, and production of infectious transcripts. Microb Pathog 7:381–388 [CrossRef]
    [Google Scholar]
  24. McAllister A., Tangy F., Aubert C., Brahic M. 1990; Genetic mapping of the ability of Theiler's virus to persist and demyelinate. J Virol 64:4252–4257
    [Google Scholar]
  25. Mena I., Roussarie J.-P., Brahic M. 2004; Infection of macrophage primary cultures by persistent and nonpersistent strains of Theiler's virus: role of capsid and noncapsid viral determinants. J Virol 78:13356–13361 [CrossRef]
    [Google Scholar]
  26. Michiels T., Jarousse N., Brahic M. 1995; Analysis of the leader and capsid coding regions of persistent and neurovirulent strains of Theiler's virus. Virology 214:550–558 [CrossRef]
    [Google Scholar]
  27. Michiels T., Dejong V., Rodrigus R., Shaw-Jackson C. 1997; Protein 2A is not required for Theiler's virus replication. J Virol 71:9549–9556
    [Google Scholar]
  28. Ohara Y., Stein S., Fu J., Stillman L., Klaman L., Roos R. P. 1988; Molecular cloning and sequence determination of DA strain of Theiler's murine encephalomyelitis viruses. Virology 164:245–255 [CrossRef]
    [Google Scholar]
  29. Ohsawa K., Watanabe Y., Miyata H., Sato H. 2003; Genetic analysis of a Theiler-like virus isolated from rats. Comp Med 53:191–196
    [Google Scholar]
  30. Palmenberg A. C., Sgro J.-Y. 2002; Alignments and comparative profiles of picornavirus genera. In Molecular Biology of Picornaviruses pp  149–155 Edited by Semler B. L., Wimmer E. Washington, DC: American Society for Microbiology;
    [Google Scholar]
  31. Petro T. M. 2005; ERK-MAP-kinases differentially regulate expression of IL-23 p19 compared with p40 and IFN- β in Theiler's virus-infected RAW264.7 cells. Immunol Lett 97:47–53 [CrossRef]
    [Google Scholar]
  32. Pevear D. C., Calenoff M., Rozhon E., Lipton H. L. 1987; Analysis of the complete nucleotide sequence of the picornavirus Theiler's murine encephalomyelitis virus indicates that it is closely related to cardioviruses. J Virol 61:1507–1516
    [Google Scholar]
  33. Pevear D. C., Borkowski J., Calenoff M., Oh C. K., Ostrowski B., Lipton H. L. 1988; Insights into Theiler's virus neurovirulence based on a genomic comparison of the neurovirulent GDVII and less virulent BeAn strains. Virology 165:1–12 [CrossRef]
    [Google Scholar]
  34. Pritchard A. E., Strom T., Lipton H. L. 1992; Nucleotide sequence identifies Vilyuisk virus as a divergent Theiler's virus. Virology 191:469–472 [CrossRef]
    [Google Scholar]
  35. Roos R. P., Kong W.-P., Semler B. L. 1989; Polyprotein processing of Theiler's murine encephalomyelitis virus. J Virol 63:5344–5353
    [Google Scholar]
  36. Shaw-Jackson C., Michiels T. 1999; Absence of internal ribosome entry site-mediated tissue specificity in the translation of a bicistronic transgene. J Virol 73:2729–2738
    [Google Scholar]
  37. Takata H., Obuchi M., Yamamoto J., Odagiri T., Roos R. P., Iizuka H., Ohara Y. 1998; L* protein of the DA strain of Theiler's murine encephalomyelitis virus is important for virus growth in a murine macrophage-like cell line. J Virol 72:4950–4955
    [Google Scholar]
  38. Tangy F., McAllister A., Brahic M. 1989; Molecular cloning of the complete genome of strain GDVII of Theiler's virus and production of infectious transcripts. J Virol 63:1101–1106
    [Google Scholar]
  39. Theiler M., Gard S. 1940; Encephalomyelitis of mice. I. Characteristics and pathogenesis of the virus. J Exp Med 72:49–67 [CrossRef]
    [Google Scholar]
  40. van Eyll O., Michiels T. 2000; Influence of the Theiler's virus L* protein on macrophage infection, viral persistence, and neurovirulence. J Virol 74:9071–9077 [CrossRef]
    [Google Scholar]
  41. van Eyll O., Michiels T. 2002; Non-AUG-initiated internal translation of the L* protein of Theiler's virus and importance of this protein for viral persistence. J Virol 76:10665–10673 [CrossRef]
    [Google Scholar]
  42. van Pesch V., van Eyll O., Michiels T. 2001; The leader protein of Theiler's virus inhibits immediate-early alpha/beta interferon production. J Virol 75:7811–7817 [CrossRef]
    [Google Scholar]
  43. Yoneyama M., Suhara W., Fukuhara Y., Fukuda M., Nishida E., Fujita T. 1998; Direct triggering of the type I interferon system by virus infection: activation of a transcription factor complex containing IRF-3 and CBP/p300. EMBO J 17:1087–1095 [CrossRef]
    [Google Scholar]
  44. Zoll J., Galama J. M. D., van Kuppeveld F. J. M., Melchers W. J. G. 1996; Mengovirus leader is involved in the inhibition of host cell protein synthesis. J Virol 70:4948–4952
    [Google Scholar]
  45. Zoll J., Melchers W. J. G., Galama J. M. D., van Kuppeveld F. J. M. 2002; The mengovirus leader protein suppresses alpha/beta interferon production by inhibition of the iron/ferritin-mediated activation of NF- κ B. J Virol 76:9664–9672 [CrossRef]
    [Google Scholar]
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