Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Viral security proteins: counteracting host defences

Nature Reviews Microbiology volume 8, pages 867–878 (2010)Cite this article

Subjects

Key Points

  • Viral reproduction involves not only replication but also interactions with host defences. Although various viral proteins can take part in counteracting innate and adaptive immunity, many viruses possess a subset of proteins that are specifically dedicated to counter-defensive activities. These proteins are sometimes referred to as 'virulence factors', but here we argue that the term 'security proteins' is preferable, for several reasons.

  • The concept of security proteins of RNA-containing viruses can be considered using the leader (L and L*) and 2A proteins of picornaviruses as examples. The picornaviruses are a large group of human and animal viruses that include important pathogens such as poliovirus, hepatitis A virus and foot-and-mouth disease virus. The genomes of different picornaviruses have a similar organization, in which the genes for L and 2A occupy fixed positions upstream and downstream of the capsid genes, respectively.

  • Both L and 2A are extremely heterogeneous with respect to size, sequence and biochemical properties. The similarly named proteins can be completely unrelated to each other in different viral genera, and the variation can be striking even among members of the same genus. A subset of picornaviruses lacks L altogether.

  • The properties and functions of L and 2A of many picornaviruses are unknown, but in those viruses that have been investigated sufficiently it has been found that these proteins can switch off various aspects of host macromolecular synthesis and specifically suppress mechanisms involved in innate immunity. Thus, notwithstanding their unrelatedness, the security proteins carry out similar biological functions. It is proposed that other picornavirus L and 2A proteins that have not yet been investigated should also be primarily involved in security activities.

  • The L, L* and 2A proteins are dispensable for viral reproduction, but their elimination or inactivation usually renders the viruses less pathogenic. The phenotypic changes associated with inactivation of security proteins are much less pronounced in cells or organisms that have innate immunity deficiencies. In several examples, the decreased fitness of a virus in which a security protein has been inactivated could be rescued by the experimental introduction of an unrelated security protein.

  • It can be argued that L and 2A were acquired by different picornaviruses independently, and possibly by exploiting different mechanisms, late in the evolution of this viral family.

  • It is proposed that the concept of security proteins is of general relevance and can be applied to viruses other than picornaviruses. The hallmarks of security proteins are: structural and biochemical unrelatedness in related viruses or even absence in some of them; dispensability of the entire protein or its functional domains for viral viability; and, for mutated versions of the proteins, fewer detrimental effects on viral reproduction in immune-compromised hosts than in immune-competent hosts.

Abstract

Interactions with host defences are key aspects of viral infection. Various viral proteins perform counter-defensive functions, but a distinct class, called security proteins, is dedicated specifically to counteracting host defences. Here, the properties of the picornavirus security proteins L and 2A are discussed. These proteins have well-defined positions in the viral polyprotein, flanking the capsid precursor, but they are structurally and biochemically unrelated. Here, we consider the impact of these two proteins, as well as that of a third security protein, L*, on viral reproduction, pathogenicity and evolution. The concept of security proteins could serve as a paradigm for the dedicated counter-defensive proteins of other viruses.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Leader and 2A proteins of picornaviruses.
Figure 2: Relationships between the presence of distinct security proteins and other evolutionary hallmarks of picornaviruses.
Figure 3: Major biological functions of the best studied but unrelated security proteins.

Similar content being viewed by others

References

  1. Lai, M. M. RNA replication without RNA-dependent RNA polymerase: surprises from hepatitis delta virus. J. Virol. 79, 7951–7958 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Solorzano, A., Rodríguez-Cousiño, N., Esteban, R. & Fujimura, T. Persistent yeast single-stranded RNA viruses exist in vivo as genomic RNA·RNA polymerase complexes in 1:1 stoichiometry. J. Biol. Chem. 275, 26428–26435 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Wang, A. L., Yang, H. M., Shen, K. A. & Wang, C. C. Giardiavirus double-stranded RNA genome encodes a capsid polypeptide and a gag-pol-like fusion protein by a translation frameshift. Proc. Natl Acad. Sci. USA 90, 8595–8599 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Koonin, E. V., Wolf, Y. I., Nagasaki K. & Dolja V. V. The Big Bang of picorna-like virus evolution antedates the radiation of eukaryotic supergroups. Nature Rev. Microbiol. 6, 925–939 (2008).

    Article  CAS  Google Scholar 

  5. Romanova, L. I. et al. Antiapoptotic activity of the cardiovirus leader protein, a viral “security” protein. J. Virol. 83, 7273–7284 (2009). The proposal to consider L and 2A proteins of picornaviruses as a distinct class of counter-defensive 'security proteins'.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Grubman, M. J., Moraes, M. P., Diaz-San Segundo, F., Pena, L. & de los Santos, T. Evading the host immune response: how foot-and-mouth disease virus has become an effective pathogen. FEMS Immunol. Med. Microbiol. 53, 8–17 (2008). A review considering, among other topics, counter-defensive functions of aphthovirus L protein.

    Article  CAS  PubMed  Google Scholar 

  7. Toyoda, H. et al. A second virus-encoded proteinase involved in proteolytic processing of poliovirus polyprotein. Cell 45, 761–770 (1986). The discovery of the proteolytic activity of enterovirus 2A.

    Article  CAS  PubMed  Google Scholar 

  8. Bazan, J. F. & Fletterick, R. J. Viral cysteine proteases are homologous to the trypsin-like family of serine proteases: structural and functional implications. Proc. Natl Acad. Sci. USA 85, 7872–7876 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gorbalenya, A. E., Koonin, E. V. & Lai, M. M. Putative papain-related thiol proteases of positive-strand RNA viruses. Identification of rubi- and aphthovirus proteases and delineation of a novel conserved domain associated with proteases of rubi-, alpha- and coronaviruses. FEBS Lett. 288, 201–205 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Beck, E., Forss, S., Strebel, K., Cattaneo, R. & Feil, G. Structure of the FMDV translation initiation site and of the structural proteins. Nucleic Acids Res. 11, 7873–7885 (1983). The identification of the L protein in FMDV.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Strebel, K. & Beck, E. A second protease of foot-and-mouth disease virus. J. Virol. 58, 893–899 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Medina, M., Domingo, E., Brangwyn, J. K. & Belsham, G. J. The two species of the foot-and-mouth disease virus leader protein, expressed individually, exhibit the same activities. Virology 194, 355–359 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Hinton, T. M., Ross-Smith, N., Warner, S., Belsham, G. J. & Crabb, B. S. Conservation of L and 3C proteinase activities across distantly related aphthoviruses. J. Gen. Virol. 83, 3111–3121 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Oberste, M. S., Maher, K. & Pallansch, M. A. Genomic evidence that simian virus 2 and six other simian picornaviruses represent a new genus in Picornaviridae. Virology 314, 283–293 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Ryan, M. D., King, A. M. Q. & Thomas G. P. Cleavage of foot-and-mouth disease virus polyprotein is mediated by residues located within a 19 amino acid sequence. J. Gen. Virol. 72, 2727–2732 (1991).

    Article  CAS  PubMed  Google Scholar 

  16. Doronina, V. A. et al. Site-specific release of nascent chains from ribosomes at a sense codon. Mol. Cell. Biol. 28, 4227–4239 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wutz, G. et al. Equine rhinovirus serotypes 1 and 2: relationship to each other and to aphthoviruses and cardioviruses. J. Gen. Virol. 77, 1719–1730 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Doherty, M., Todd, D., McFerran, N. & Hoey, E. M. Sequence analysis of a porcine enterovirus serotype 1 isolate: relationships with other picornaviruses. J. Gen. Virol. 80, 1929–1941 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Hales, L. M. et al. Complete genome sequence analysis of Seneca Valley virus-001, a novel oncolytic picornavirus. J. Gen. Virol. 89, 1265–1275 (2008).

    CAS  Google Scholar 

  20. Kapoor, A. et al. A highly prevalent and genetically diversified Picornaviridae genus in South Asian children. Proc. Natl Acad. Sci. USA 105, 20482–20487 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Johansson, S., Niklasson, B., Maizel, J., Gorbalenya, A. E. & Lindberg, A. M. Molecular analysis of three Ljungan virus isolates reveals a new, close-to-root lineage of the Picornaviridae with a cluster of two unrelated 2A proteins. J. Virol. 76, 8920–8930 (2002). The first description of two unrelated 2A proteins in a picornavirus, and a discussion of the relationships between L and 2A in different picornaviruses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ding, C. & Zhang, D. Molecular analysis of duck hepatitis virus type 1. Virology 361, 9–17 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Kapoor, A. et al. A highly divergent picornavirus in a marine mammal. J. Virol. 82, 311–320 (2008).

    Article  CAS  Google Scholar 

  24. Donnelly, M. L. L., Gani, D., Flint, M., Monoghan, S. & Ryan, M. D. The cleavage activity of aphtho- and cardiovirus 2A proteins. J. Gen. Virol. 78, 13–21 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Kazachkov, Y. A., Svitkin, Y. V. & Agol, V. I. The position of polypeptide G on the encephalomyocarditis virus polyprotein cleavage map. FEBS Lett. 154, 161–165 (1983).

    Article  CAS  PubMed  Google Scholar 

  26. Gorbalenya, A. E., Chumakov, K. M. & Agol, V. I. RNA-binding properties of nonstructural polypeptide G of encephalomyocarditis virus. Virology 88, 183–185 (1978).

    Article  CAS  PubMed  Google Scholar 

  27. Hughes, P. J. & Stanway, G. The 2A proteins of three diverse picornaviruses are related to each other and to the H-rev107 family of proteins involved in the control of cell proliferation. J. Gen. Virol. 81, 201–207 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Kazachkov, Y. A. et al. Leader polypeptides encoded in the 5′-region of the encephalomyocarditis virus genome. FEBS Lett. 141, 153–156 (1982). The discovery of cardiovirus L protein, the first leader protein to be found for picornaviruses.

    Article  CAS  PubMed  Google Scholar 

  29. Chen, H. H., Kong, W. P. & Roos, R. P. The leader peptide of Theiler's murine encephalomyelitis virus is a zinc-binding protein. J. Virol. 69, 8076–8078 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Cornilescu, C. C., Porter, F. W., Zhao, K. Q., Palmenberg, A. C. & Markley, J. L. NMR structure of the mengovirus Leader protein zinc-finger domain. FEBS Lett. 582, 896–900 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Dvorak, C. M. et al. Leader protein of encephalomyocarditis virus binds zinc, is phosphorylated during viral infection, and affects the efficiency of genome translation. Virology 290, 261–271 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Zoll, J., Melchers, W. J., Galama, J. M. & van Kuppeveld, F. J. The mengovirus leader protein suppresses α/β interferon production by inhibition of the iron/ferritin-mediated activation of NF-κB. J. Virol. 76, 9664–9672 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kong, W. P. & Roos, R. P. Alternative translation initiation site in the DA strain of Theiler's murine encephalomyelitis virus. J. Virol. 65, 3395–3399 (1991). The discovery of L*.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Chen, H. H., Kong, W. P., Zhang, L., Ward, P. L. & Roos, R. P. A picornaviral protein synthesized out of frame with the polyprotein plays a key role in a virus-induced immune-mediated demyelinating disease. Nature Med. 1, 927–931 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Bernstein, H. D., Sonenberg N. & Baltimore D. Poliovirus mutant that does not selectively inhibit host cell protein synthesis. Mol. Cell. Biol. 5, 2913–2923 (1985). The demonstration that enterovirus 2Apro cleaves a translation initiation factor.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kräusslich, H. G., Nicklin, M. J., Toyoda, H., Etchison, D. & Wimmer, E. Poliovirus proteinase 2A induces cleavage of eucaryotic initiation factor 4F polypeptide p220. J. Virol. 61, 2711–2718 (1987).

    PubMed  PubMed Central  Google Scholar 

  37. Liebig, H. et al. Purification of two picornaviral 2A proteinases: interaction with eIF4γ and influence on translation. Biochemistry 32, 7581–7588 (1993).

    Article  CAS  PubMed  Google Scholar 

  38. Chau, D. H. et al. Coxsackievirus B3 proteases 2A and 3C induce apoptotic cell death through mitochondrial injury and cleavage of eIF4GI but not DAP5/p97/NAT1. Apoptosis 12, 513–524 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Devaney, M. A., Vakharia, V. N., Lloyd, R. E., Ehrenfeld, E. & Grubman, M. J. 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 (1988). The finding that aphthovirus Lpro can cleave a translation initiation factor.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Joachims, M., van Breugel, P. C. & Lloyd, R. E. Cleavage of poly(A)-binding protein by enterovirus proteases concurrent with inhibition of translation in vitro. J. Virol. 73, 718–727 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Kerekatte, V. et al. Cleavage of poly(A)-binding protein by coxsackievirus 2A protease in vitro and in vivo: another mechanism for host protein synthesis shutoff? J. Virol. 73, 709–717 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Zoll, J., van Kuppeveld, F. J., Galama, J. M. & Melchers, W. J. Genetic analysis of mengovirus protein 2A: its function in polyprotein processing and virus reproduction. J. Gen. Virol. 79, 17–25 (1998).

    Article  CAS  PubMed  Google Scholar 

  43. Svitkin, Y. V., Hahn, H., Gingras, A. C., Palmenberg, A. C. & Sonenberg, N. Rapamycin and wortmannin enhance replication of a defective encephalomyocarditis virus. J. Virol. 72, 5811–5819 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Medvedkina, O. A., Scarlat, I. V., Kalinina, N. O. & Agol, V. I. Virus-specific proteins associated with ribosomes of Krebs II cells infected with encephalomyocarditis virus. FEBS Lett. 39, 4–8 (1974).

    Article  CAS  PubMed  Google Scholar 

  45. Groppo, R. & Palmenberg, A. C. Cardiovirus 2A protein associates with 40S but not 80S ribosome subunits during infection. J. Virol. 81, 13067–13074 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Aminev, A. G., Amineva S. P. & Palmenberg, A. C. Encephalomyocarditis viral protein 2A localizes to nucleoli and inhibits cap-dependent mRNA translation. Virus Res. 95, 45–57 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Aminev, A. G., Amineva. S. P. & Palmenberg A. C. Encephalomyocarditis virus (EMCV) proteins 2A and 3BCD localize to nuclei and inhibit cellular mRNA transcription but not rRNA transcription. Virus Res. 95, 59–73 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Zoll, J., Galama, J. M., van Kuppeveld, F. J. & Melchers, W. J. Mengovirus leader is involved in the inhibition of host cell protein synthesis. J. Virol. 70, 4948–4952 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Porter, F. W., Bochkov, Y. A., Albee, A. J., Wiese, C. & Palmenberg, A. C. A picornavirus protein interacts with Ran-GTPase and disrupts nucleocytoplasmic transport. Proc. Natl Acad. Sci. USA 103, 12417–12422 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ricour, C. et al. Inhibition of mRNA export and dimerization of interferon regulatory factor 3 by Theiler's virus leader protein. J. Gen. Virol. 90, 177–186 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Maltese, E. et al. Inhibition of cap-dependent gene expression induced by protein 2A of hepatitis A virus. J. Gen. Virol. 81, 1373–1381 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Yalamanchili, P., Banerjee, R. & Dasgupta, A. Poliovirus-encoded protease 2APro cleaves the TATA-binding protein but does not inhibit host cell RNA polymerase II transcription in vitro. J. Virol. 71, 6881–6886 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Davies, M. V., Pelletier, J., Meerovitch, K., Sonenberg, N. & Kaufman, R. J. The effect of poliovirus proteinase 2Apro expression on cellular metabolism. Inhibition of DNA replication, RNA polymerase II transcription, and translation. J. Biol. Chem. 266, 14714–14720 (1991).

    CAS  PubMed  Google Scholar 

  54. Almstead, L. L. & Sarnow, P. Inhibition of U snRNP assembly by a virus-encoded proteinase. Genes Dev. 21, 1086–1097 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. de los Santos T., Diaz-San Segundo, F. & Grubman, M. J. Degradation of nuclear factor kappa B during foot-and-mouth disease virus infection. J. Virol. 81, 12803–12815 (2007).

    Article  CAS  Google Scholar 

  56. de los Santos, T. et al. A conserved domain in the leader proteinase of foot-and-mouth disease virus is required for proper subcellular localization and function. J. Virol. 83, 1800–1810 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Krogerus, C., Samuilova, O., Poyry, T., Jokitalo, E. & Hyypia, T. Intracellular localization and effects of individually expressed human parechovirus 1 non-structural proteins. J. Gen. Virol. 88, 831–841 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Seipelt, J., Liebig, H. D., Sommergruber, W., Gerner, C. & Kuechler, E. 2A proteinase of human rhinovirus cleaves cytokeratin 8 in infected HeLa cells. J. Biol. Chem. 275, 20084–20089 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Badorff, C. et al. Enteroviral protease 2A cleaves dystrophin: evidence of cytoskeletal disruption in an acquired cardiomyopathy. Nature Med. 5, 320–326 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Belov, G. A. et al. Bidirectional increase in permeability of nuclear envelope upon poliovirus infection and accompanying alterations of nuclear pores. J. Virol. 78, 10166–10177 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Park, N., Katikaneni, P., Skern, T. & Gustin, K. E. Differential targeting of nuclear pore complex proteins in poliovirus-infected cells. J. Virol. 82, 1647–1655 (2008).

    Article  CAS  Google Scholar 

  62. Castelló, A., Izquierdo, J. M., Welnowska, E. & Carrasco, L. RNA nuclear export is blocked by poliovirus 2A protease and is concomitant with nucleoporin cleavage. J. Cell Sci. 122, 3799–3809 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Delhaye, S., van Pesch, V. & Michiels T. The leader protein of Theiler's virus interferes with nucleocytoplasmic trafficking of cellular proteins. J. Virol. 78, 4357–4362 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lidsky, P. V. et al. Nucleo-cytoplasmic traffic disorder induced by cardioviruses. J. Virol. 80, 2705–2717 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bardina, M. V. et al. Mengovirus-induced rearrangement of the nuclear pore complex: hijacking cellular phosphorylation machinery. J. Virol. 83, 3150–3161 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Porter, F. W. & Palmenberg, A. C. Leader-induced phosphorylation of nucleoporins correlates with nuclear trafficking inhibition by cardioviruses. J. Virol. 83, 1941–1951 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Chinsangaram, J., Piccone, M. E. & Grubman, M. J. Ability of foot-and-mouth disease virus to form plaques in cell culture is associated with suppression of alpha/beta interferon. J. Virol. 73, 9891–9898 (1999).

    CAS  Google Scholar 

  68. Chinsangaram, J., Koster, M. & Grubman, M. J. Inhibition of L-deleted foot-and-mouth disease virus replication by α/β interferon involves double-stranded RNA-dependent protein kinase. J. Virol. 75, 5498–5503 (2001).

    Article  CAS  Google Scholar 

  69. de los Santos, T., de Avila Botton, S., Weiblen, R. & Grubman, M. J. The leader proteinase of foot-and-mouth disease virus inhibits the induction of beta interferon mRNA and blocks the host innate immune response. J. Virol. 80, 1906–1914 (2006).

    Article  CAS  Google Scholar 

  70. Morrison, J. M. & Racaniello V. R. Proteinase 2Apro is essential for enterovirus replication in type I interferon-treated cells. J. Virol. 83, 4412–4422 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Drahos, J. & Racaniello, V. R. Cleavage of IPS-1 in cells infected with human rhinovirus. J. Virol. 83, 11581–11587 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Graham, K. L. et al. Proteolytic cleavage of the catalytic subunit of DNA-dependent protein kinase during poliovirus infection. J. Virol. 78, 6313–6321 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. van Pesch, V., van Eyll, O. & Michiels, T. The leader protein of Theiler's virus inhibits immediate-early alpha/beta interferon production. J. Virol. 75, 7811–7817 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hato, S. V. et al. The mengovirus leader protein blocks interferon-a/b gene transcription and inhibits activation of interferon regulatory factor 3. Cell. Microbiol. 9, 2921–2930 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Lin, X., Roos, R. P., Pease, L. R., Wettstein, P. & Rodriguez, M. A Theiler's virus alternatively initiated protein inhibits the generation of H-2K-restricted virus-specific cytotoxicity. J. Immunol. 162, 17–24 (1999).

    CAS  PubMed  Google Scholar 

  76. Lin, X., Ma X., Rodriguez, M. & Roos, R. P. CD4 T cells are important for clearance of the DA strain of TMEV from the central nervous system of SJL/J mice. Int. Immunol. 16, 1237–1240 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Kong, W. P., Ghadge, G. D. & Roos, R. P. Involvement of cardiovirus leader in host cell-restricted virus expression. Proc. Natl Acad. Sci. USA 91, 1796–1800 (1994). This work demonstrates that cardiovirus L is dispensable.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Calenoff, M. A., Badshah, C. S., Dal Canto, M. C., Lipton, H. L. & Rundell, M. K. The leader polypeptide of Theiler's virus is essential for neurovirulence but not for virus growth in BHK cells. J. Virol. 69, 5544–5549 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Michiels, T., Dejong, V., Rodrigus, R. & Shaw-Jackson, C. Protein 2A is not required for Theiler's virus replication. J. Virol. 71, 9549–9556 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Takata, H. et al. 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 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. van Eyll, O. & Michiels, T. Influence of the Theiler's virus L* protein on macrophage infection, viral persistence, and neurovirulence. J. Virol. 74, 9071–9077 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Goldstaub, D. et al. Poliovirus 2A protease induces apoptotic cell death. Mol. Cell. Biol. 20, 1271–1277 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kuo, R. L., Kung, S. H., Hsu, Y. Y. & Liu, W. T. Infection with enterovirus 71 or expression of its 2A protease induces apoptotic cell death. J. Gen. Virol. 83, 1367–1376 (2002).

    Article  CAS  PubMed  Google Scholar 

  84. Neznanov, N. et al. Poliovirus protein 3A inhibits tumor necrosis factor (TNF)-induced apoptosis by eliminating the TNF receptor from the cell surface. J. Virol. 75, 10409–10420 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Burgon, T. B., Jenkins, J. A., Deitz, S. B., Spagnolo, J. F. & Kirkegaard, K. Bypass suppression of small-plaque phenotypes by mutation in poliovirus 2A that enhances apoptosis. J. Virol. 83, 10129–10139 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Igarashi, H. et al. 2Aprotease is not a prerequisite for poliovirus replication. J. Virol. 84, 5947–5957 (2010). The finding that enterovirus 2A is dispensable.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Fan, J., Son, K. N., Arslan, S. Y., Liang, Z. & Lipton, H. L. Theiler's murine encephalomyelitis virus leader protein is the only nonstructural protein tested that induces apoptosis when transfected into mammalian cells. J. Virol. 83, 6546–6553 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ghadge, G. D., Ma, L., Sato, S., Kim, J. & Roos, R. P. 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 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Brown, C. C., Piccone, M. E., Mason, P. W., McKenna, T. S. & Grubman, M. J. Pathogenesis of wild-type and leaderless foot-and-mouth disease virus in cattle. J. Virol. 70, 5638–5641 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Paul, S. & Michiels, T. Cardiovirus leader proteins are functionally interchangeable and have evolved to adapt to virus replication fitness. J. Gen. Virol. 87, 1237–1246 (2006).

    Article  CAS  PubMed  Google Scholar 

  91. Sakoda, Y., Ross-Smith N., Inoue, T. & Belsham, G. J. An attenuating mutation in the 2A protease of swine vesicular disease virus, a picornavirus, regulates cap- and internal ribosome entry site-dependent protein synthesis. J. Virol. 75, 10643–10650 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Piccone, M. E., Chen, H. H., Roos, R. P. & Grubman, M. J. Construction of a chimeric Theiler's murine encephalomyelitis virus containing the leader gene of foot-and-mouth disease virus. Virology 226, 135–139 (1996).

    Article  CAS  PubMed  Google Scholar 

  93. Hato, S. V. et al. Differential IFN-α/β production suppressing capacities of the leader proteins of mengovirus and foot-and-mouth disease virus. Cell. Microbiol. 12, 310–317 (2010).

    Article  CAS  PubMed  Google Scholar 

  94. Stavrou, S. et al. Theiler's murine encephalomyelitis virus (TMEV) L* amino acid position 93 is important for virus persistence and virus-induced demyelination. J. Virol. 84, 1348–1354 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Piccone, M. E., Rieder, E., Mason, P. W. & Grubman, M. J. The foot-and-mouth disease virus leader proteinase gene is not required for viral replication. J. Virol. 69, 5376–5382 (1995). An article showing that aphthovirus L is dispensable.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Harmon, S., Emerson, S. U., Huang, Y. K., Summers, D. F. & Ehrenfeld, E. Hepatitis A viruses with deletions in the 2A gene are infectious in cultured cells and marmosets. J. Virol. 69, 5576–5581 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Cohen, L., Bénichou, D. & Martin, A. Analysis of deletion mutants indicates that the 2A polypeptide of hepatitis A virus participates in virion morphogenesis. J. Virol. 76, 7495–7505 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Molla, A., Paul, A. V., Schmid, M., Jang, S. K. & Wimmer, E. Studies on dicistronic polioviruses implicate viral proteinase 2Apro in RNA replication. Virology 196, 739–747 (1993).

    Article  CAS  PubMed  Google Scholar 

  99. Dasgupta, A. et al. in Molecular Biology of Picornaviruses (eds Semler, B. L. & Wimmer, E.) 321–333 (American Society for Microbiology Press, Washington DC, 2002).

    Google Scholar 

  100. Neznanov, N. et al. Proteolytic cleavage of the p65-RelA subunit of NF-κB during poliovirus infection. J. Biol. Chem. 280, 24153–24158 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Yang, Y. et al. Disruption of innate immunity due to mitochondrial targeting of a picornaviral protease precursor. Proc. Natl Acad. Sci. USA 104, 7253–7258 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Barral, P. M., Sarkar, D., Fisher, P. B. & Racaniello, V. R. RIG-I is cleaved during picornavirus infection. Virology 391, 171–176 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Egger, D., Gossert, R. & Bienz, K. in Molecular Biology of Picornaviruses (eds Semler, B. & Wimmer, E.) 247–253 (American Society for Microbiology Press, Washington DC, 2002).

    Google Scholar 

  104. Doedens, J. R. & Kirkegaard, K. Inhibition of cellular protein secretion by poliovirus proteins 2B and 3A. EMBO J. 14, 894–907 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Kemball, C. C. et al. Coxsackievirus B3 inhibits antigen presentation in vivo, exerting a profound and selective effect on the MHC class I pathway. PLoS Pathog. 5, e1000618 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Pacheco, J. M., Henry, T. M., O'Donnell, V. K., Gregory, J. B. & Mason, P. W. Role of nonstructural proteins 3A and 3B in host range and pathogenicity of foot-and-mouth disease virus. J. Virol. 77, 13017–13027 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Autret, A. et al. Early phosphatidylinositol 3-kinase/Akt pathway activation limits poliovirus-induced JNK-mediated cell death. J. Virol. 82, 3796–3802 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ziegler, E., Borman, A. M., Kirchweger, R., Skern, T. & Kean, K. M. Foot-and-mouth disease virus Lb proteinase can stimulate rhinovirus and enterovirus IRES-driven translation and cleave several proteins of cellular and viral origin. J. Virol. 69, 3465–3474 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Ohlmann, T., Rau, M., Pain, V. M. & Morley, S. J. The C-terminal domain of eukaryotic protein synthesis initiation factor (eIF) 4G is sufficient to support cap-independent translation in the absence of eIF4E. EMBO J. 15, 1371–1382 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Jurgens, C. K. et al. 2Apro is a multifunctional protein that regulates the stability, translation and replication of poliovirus RNA. Virology 345, 346–357 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Rowe, A., Ferguson, G. L., Minor, P. D. & Macadam, A. J. Coding changes in the poliovirus protease 2A compensate for 5′NCR domain V disruptions in a cell-specific manner. Virology 269, 284–293 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Li, X., Lu, H. H., Mueller, S. & Wimmer, E. The C-terminal residues of poliovirus proteinase 2Apro are critical for viral RNA replication but not for cis- or trans-proteolytic cleavage. J. Gen. Virol. 82, 397–408 (2001).

    Article  CAS  PubMed  Google Scholar 

  113. Collis, P. S., O'Donnell, B. J., Barton, D. J., Rogers, J. A. & Flanegan, J. B. Replication of poliovirus RNA and subgenomic RNA transcripts in transfected cells. J. Virol. 66, 6480–6488 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Sasaki, J. & Taniguchi, K. Aichi virus 2A protein is involved in viral RNA replication. J. Virol., 82, 9765–9769 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Probst, C., Jecht, M. & Gauss-Müller, V. Intrinsic signals for the assembly of hepatitis A virus particles. Role of structural proteins VP4 and 2A. J. Biol. Chem. 274, 4527–4531 (1999).

    CAS  Google Scholar 

  116. Anderson, D. A. & Ross, B. Morphogenesis of hepatitis A virus: isolation and characterization of subviral particles. J. Virol. 64, 5284–5289 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Martin, A. et al. Identification and site-directed mutagenesis of the primary (2A/2B) cleavage site of the hepatitis A virus polyprotein: functional impact on the infectivity of HAV RNA transcripts. Virology 213, 213–222 (1995).

    Article  CAS  PubMed  Google Scholar 

  118. Morace, G., Kusov, Y., Dzagurov, G., Beneduce, F. & Gauss-Muller, V. The unique role of domain 2A of the hepatitis A virus precursor polypeptide P1–2A in viral morphogenesis. BMB Rep. 41, 678–683 (2008).

    Article  CAS  PubMed  Google Scholar 

  119. Le Gall, O. et al. Picornavirales, a proposed order of positive-sense single-stranded RNA viruses with a pseudo-T = 3 virion architecture. Arch. Virol. 153, 715–727 (2008).

    Article  CAS  PubMed  Google Scholar 

  120. Gromeier, M., Wimmer, E. & Gorbalenya, A. E. in Origin and Evolution of Viruses (eds Domingo, E., Webster, R. & Holland, J.) 287–343 (Academic Press, San Diego, 1999).

    Google Scholar 

  121. Svitkin, Y. V. & Agol, V. I. Translational barrier in central region of encephalomyocarditis virus genome. Modulation by elongation factor 2 (eEF-2). Eur. J. Biochem. 133, 145–154 (1983).

    Article  CAS  PubMed  Google Scholar 

  122. Luke, G. A. et al. Occurrence, function and evolutionary origins of '2A-like' sequences in virus genomes. J. Gen. Virol. 89, 1036–1042 (2008). An article discussing viral translation-interrupting 2A peptides.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Atkins, J. F. et al. A case for ''StopGo'': reprogramming translation to augment codon meaning of GGN by promoting unconventional termination (Stop) after addition of glycine and then allowing continued translation (Go). RNA 13, 803–810 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zeddam, J. L. et al. Euprosterna elaeasa virus genome sequence and evolution of the Tetraviridae family: Emergence of bipartite genomes and conservation of the VPg signal with the dsRNA Birnaviridae family. Virology 397, 145–154 (2010).

    Article  CAS  PubMed  Google Scholar 

  125. Gorbalenya, A. E. in Molecular Basis of Viral Evolution (eds Gibbs, A., Calisher, C. H. & Garcia-Arenal, F.) 49–66 (Cambridge Univ. Press, Cambridge, UK, 1995).

    Book  Google Scholar 

  126. Drexler, J. F. et al. Genomic features and evolutionary constraints in Saffold-like cardioviruses. J. Gen. Virol. 91, 1418–1427 (2010).

    Article  CAS  PubMed  Google Scholar 

  127. Agol, V. I. in The Picornaviruses (eds Ehrenfeld, E., Domingo, E. & Roos, R. P.) 239–252 (ASM Press, Washington DC, 2010).

    Google Scholar 

  128. Frieman, M. & Baric, R. Mechanisms of severe acute respiratory syndrome pathogenesis and innate immunomodulation. Microbiol. Mol. Biol. Rev. 72, 672–685 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Melian, E. B. et al. NS1′ of flaviviruses in the Japanese encephalitis virus serogroup is a product of ribosomal frameshifting and plays a role in viral neuroinvasiveness. J. Virol. 84, 1641–1647 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Habjan, M. et al. NSs protein of Rift Valley fever virus induces the specific degradation of the double-stranded RNA-dependent protein kinase. J. Virol. 83, 4365–4375 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Belsham, G. J. Divergent picornavirus IRES elements. Virus Res. 139, 183–192 (2009).

    Article  CAS  PubMed  Google Scholar 

  132. Gasteiger, E. et al. in The Proteomics Protocols Handbook (ed. Walker, J. M.) 571–607 (Humana Press, Totowa, 2005).

    Book  Google Scholar 

  133. Larkin, M. A. Clustal W and Clustal X version 2.0. Bioinformatics 23, 2947–2948 (2007).

    Article  CAS  PubMed  Google Scholar 

  134. Marchler-Bauer, A. CDD: specific functional annotation with the Conserved Domain Database. Nucleic Acids Res. 37, D205–D210 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank F. van Kuppeveld for critical reading of this manuscript. Recent research in the authors' laboratory was supported by grants from the Russian Foundation for Basic Research (RFBR), the Scientific School Support Program and The Netherlands Organization for Scientific Research–RFBR (NWO–RFBR).

Author information

Authors and Affiliations

  1. M. P. Chumakov Institute of Poliomyelitis and Viral Encephalitides, Russian Academy of Medical Sciences, Moscow, 142782, Russia

    Vadim I. Agol & Anatoly P. Gmyl

  2. M. V. Lomonosov Moscow State University, Moscow, 119899, Russia

    Vadim I. Agol

Authors
  1. Vadim I. Agol
    View author publications

    Search author on:PubMed Google Scholar

  2. Anatoly P. Gmyl
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Vadim I. Agol.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Related links

Related links

FURTHER INFORMATION

GenBank

International Committee on Taxonomy of Viruses

MrBayes

Glossary

Cap-dependent translation

The mode of translation for which initiation is dependent on the presence of the so-called cap structure (m7GpppN) at the 5′ end of an mRNA. Specific cap-binding proteins (translation initiation factors) recruit the ribosome to the 5′ end of the mRNA, and the ribosome scans the template until it encounters the initiation codon. This translation mode is exploited by most mRNAs in eukaryotic cells.

Poly(A)-binding protein 1

A protein that binds to the 3′ poly(A) tail of eukaryotic mRNAs on the one hand and to cap-dependent translation initiation factors on the other hand. This dual binding results in a non-covalent circularization of the mRNA template, which is accompanied by a significant increase in translation efficiency.

Spliceosome

A complex that is formed of several small nuclear ribonucleoproteins and is involved in splicing.

U spliceosomal small nuclear RNA

An RNA component of a spliceosomal small nuclear ribonucleoprotein.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Agol, V., Gmyl, A. Viral security proteins: counteracting host defences. Nat Rev Microbiol 8, 867–878 (2010). https://doi.org/10.1038/nrmicro2452

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nrmicro2452

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing