1887

Abstract

Foot-and-mouth disease virus (FMDV) causes economically damaging infections of cloven-hooved animals, with outbreaks resulting in large financial losses to the agricultural industry. Due to the highly contagious nature of FMDV, research with infectious virus is restricted to a limited number of key facilities worldwide. FMDV sub-genomic replicons are therefore important tools for the study of viral translation and genome replication. The type III phosphatidylinositol-4-kinases (PI4Ks) are a family of enzymes that plays a key role in the production of replication complexes (viral factories) of a number of positive-sense RNA viruses and represents a potential target for novel pan-viral therapeutics. Here, we investigated whether type III PI4Ks also play a role in the FMDV life cycle, using a combination of FMDV sub-genomic replicons and bicistronic internal ribosome entry site (IRES)-containing reporter plasmids. We demonstrated that replication of the FMDV replicon was unaffected by inhibitors of either PI4KIIIα or PI4KIIIβ. However, PIK93, an inhibitor previously demonstrated to target PI4KIIIβ, did inhibit IRES-mediated protein translation. Consistent with this, cells transfected with FMDV replicons did not exhibit elevated levels of phosphatidylinositol-4-phosphate lipids. These results are therefore supportive of the hypothesis that FMDV genome replication does not require type III PI4K activity and does not activate these kinases.

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2016-09-01
2019-10-22
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References

  1. Alexandersen S., Zhang Z., Donaldson A. I..( 2002;). Aspects of the persistence of foot-and-mouth disease virus in animals the carrier problem. . Microbes Infect 4: 1099–1110. [CrossRef] [PubMed]
    [Google Scholar]
  2. Altan-Bonnet N., Balla T..( 2012;). Phosphatidylinositol 4-kinases: hostages harnessed to build panviral replication platforms. . Trends Biochem Sci 37: 293–302. [CrossRef] [PubMed]
    [Google Scholar]
  3. Arita M., Kojima H., Nagano T., Okabe T., Wakita T., Shimizu H..( 2011;). Phosphatidylinositol 4-kinase III beta is a target of enviroxime-like compounds for antipoliovirus activity. . J Virol 85: 2364–2372. [CrossRef] [PubMed]
    [Google Scholar]
  4. Belov G. A., Altan-Bonnet N., Kovtunovych G., Jackson C. L., Lippincott-Schwartz J., Ehrenfeld E..( 2007;). Hijacking components of the cellular secretory pathway for replication of poliovirus RNA. . J Virol 81: 558–567. [CrossRef] [PubMed]
    [Google Scholar]
  5. Belsham G. J., Brangwyn J. K..( 1990;). A region of the 5′ noncoding region of foot-and-mouth disease virus RNA directs efficient internal initiation of protein synthesis within cells: involvement with the role of L protease in translational control. . J Virol 64: 5389–5395.[PubMed]
    [Google Scholar]
  6. Belsham G. J..( 2009;). Divergent picornavirus IRES elements. . Virus Res 139: 183–192. [CrossRef] [PubMed]
    [Google Scholar]
  7. Bentham M., Holmes K., Forrest S., Rowlands D. J., Stonehouse N. J..( 2012;). Formation of higher-order foot-and-mouth disease virus 3D(pol) complexes is dependent on elongation activity. . J Virol 86: 2371–2374. [CrossRef] [PubMed]
    [Google Scholar]
  8. Berger K. L., Cooper J. D., Heaton N. S., Yoon R., Oakland T. E., Jordan T. X., Mateu G., Grakoui A., Randall G..( 2009;). Roles for endocytic trafficking and phosphatidylinositol 4-kinase III alpha in hepatitis C virus replication. . Proc Natl Acad Sci U S A 106: 7577–7582. [CrossRef] [PubMed]
    [Google Scholar]
  9. Berger K. L., Kelly S. M., Jordan T. X., Tartell M. A., Randall G..( 2011;). Hepatitis C virus stimulates the phosphatidylinositol 4-kinase III alpha-dependent phosphatidylinositol 4-phosphate production that is essential for its replication. . J Virol 85: 8870–8883. [CrossRef] [PubMed]
    [Google Scholar]
  10. Berryman S., Brooks E., Burman A., Hawes P., Roberts R., Netherton C., Monaghan P., Whelband M., Cottam E. et al.( 2012;). Foot-and-mouth disease virus induces autophagosomes during cell entry via a class III phosphatidylinositol 3-kinase-independent pathway. . J Virol 86: 12940–12953. [CrossRef] [PubMed]
    [Google Scholar]
  11. Berryman S., Moffat K., Harak C., Lohmann V., Jackson T..( 2016;). Foot-and-mouth disease virus replicates independently of phosphatidylinositol 4-phosphate and type III phosphatidylinositol 4-kinases. . J Gen Virol 97: 1841–1852. [CrossRef] [PubMed]
    [Google Scholar]
  12. Bishé B., Syed G., Siddiqui A..( 2012;). Phosphoinositides in the hepatitis C virus life cycle. . Viruses 4: 2340–2358. [CrossRef] [PubMed]
    [Google Scholar]
  13. Borawski J., Troke P., Puyang X., Gibaja V., Zhao S., Mickanin C., Leighton-Davies J., Wilson C. J., Myer V. et al.( 2009;). Class III phosphatidylinositol 4-kinase alpha and beta are novel host factor regulators of hepatitis C virus replication. . J Virol 83: 10058–10074. [CrossRef] [PubMed]
    [Google Scholar]
  14. den Boon J. A., Ahlquist P..( 2010;). Organelle-like membrane compartmentalization of positive-strand RNA virus replication factories. . Annu Rev Microbiol 64: 241–256. [CrossRef] [PubMed]
    [Google Scholar]
  15. 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.[PubMed]
    [Google Scholar]
  16. Dorobantu C. M., van der Schaar H. M., Ford L. A., Strating J. R., Ulferts R., Fang Y., Belov G., van Kuppeveld F. J., Sandri-Goldin R. M..( 2014;). Recruitment of PI4KIIIβ to coxsackievirus B3 replication organelles is independent of ACBD3, GBF1, and Arf1. . J Virol 88: 2725–2736. [CrossRef] [PubMed]
    [Google Scholar]
  17. Dorobantu C. M., Albulescu L., Harak C., Feng Q., van Kampen M., Strating J. R. P. M., Gorbalenya A. E., Lohmann V., van der Schaar H. M., van Kuppeveld F. J. M..( 2015a;). Modulation of the host lipid landscape to promote RNA virus replication: the picornavirus encephalomyocarditis virus converges on the pathway used by hepatitis C virus. . PLoS Pathog 11: e1005185. [CrossRef]
    [Google Scholar]
  18. Dorobantu C. M., Ford-Siltz L. A., Sittig S. P., Lanke K. H. W., Belov G. A., van Kuppeveld F. J. M., van der Schaar H. M..( 2015b;). GBF1- and ACBD3-independent recruitment of PI4KIIIβ to replication sites by rhinovirus 3A proteins. . Journal of Virology 89: 1913–1918. [CrossRef]
    [Google Scholar]
  19. Forrest S., Lear Z., Herod M. R., Ryan M., Rowlands D. J., Stonehouse N. J..( 2014;). Inhibition of the foot-and-mouth disease virus subgenomic replicon by RNA aptamers. . J Gen Virol 95: 2649–2657. [CrossRef] [PubMed]
    [Google Scholar]
  20. Gosert R., Egger D., Lohmann V., Bartenschlager R., Blum H. E., Bienz K., Moradpour D..( 2003;). Identification of the hepatitis C virus RNA replication complex in Huh-7 cells harboring subgenomic replicons. . J Virol 77: 5487–5492. [CrossRef] [PubMed]
    [Google Scholar]
  21. Grubman M. J., Baxt B..( 2004;). Foot-and-mouth disease. . Clin Microbiol Rev 17: 465–493. [CrossRef] [PubMed]
    [Google Scholar]
  22. Herod M. R., Loundras E.-A., Ward J. C., Tulloch F., Rowlands D. J., Stonehouse N. J..( 2015;). Employing transposon mutagenesis to investigate foot-and-mouth disease virus replication. . J Gen Virol 96: 3507–3518. [CrossRef] [PubMed]
    [Google Scholar]
  23. Hsu N.-Y., Ilnytska O., Belov G., Santiana M., Chen Y. H., Takvorian P. M., Pau C., van der Schaar H., Kaushik-Basu N. et al.( 2010;). Viral reorganization of the secretory pathway generates distinct organelles for RNA replication. . Cell 141: 799–811. [CrossRef] [PubMed]
    [Google Scholar]
  24. Jones D. M., Gretton S. N., McLauchlan J., Targett-Adams P..( 2007;). Mobility analysis of an NS5A-GFP fusion protein in cells actively replicating hepatitis C virus subgenomic RNA. . J Gen Virol 88: 470–475. [CrossRef] [PubMed]
    [Google Scholar]
  25. Kirchweger R., Ziegler E., Lamphear B. J., Waters D., Liebig H. D., Sommergruber W., Sobrino F., Hohenadl C., Blaas D., Rhoads R. E..( 1994;). Foot-and-mouth disease virus leader proteinase: purification of the Lb form and determination of its cleavage site on eIF-4 gamma. . J Virol 68: 5677–5684.[PubMed]
    [Google Scholar]
  26. Knight Z. A., Gonzalez B., Feldman M. E., Zunder E. R., Goldenberg D. D., Williams O., Loewith R., Stokoe D., Balla A. et al.( 2006;). A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. . Cell 125: 733–747. [CrossRef] [PubMed]
    [Google Scholar]
  27. Lanke K. H., van der Schaar H. M., Belov G. A., Feng Q., Duijsings D., Jackson C. L., Ehrenfeld E., van Kuppeveld F. J..( 2009;). GBF1, a guanine nucleotide exchange factor for Arf, is crucial for coxsackievirus B3 RNA replication. . J Virol 83: 11940–11949. [CrossRef] [PubMed]
    [Google Scholar]
  28. Licursi M., Christian S. L., Pongnopparat T., Hirasawa K..( 2011;). In vitro and in vivo comparison of viral and cellular internal ribosome entry sites for bicistronic vector expression. . Gene Ther 18: 631–636. [CrossRef] [PubMed]
    [Google Scholar]
  29. Martínez-Salas E., Francisco-Velilla R., Fernandez-Chamorro J., Lozano G., Diaz-Toledano R..( 2015;). Picornavirus IRES elements: RNA structure and host protein interactions. . Virus Res, 1–12.
    [Google Scholar]
  30. McInerney G. M., King A. M., Ross-Smith N., Belsham G. J..( 2000;). Replication-competent foot-and-mouth disease virus RNAs lacking capsid coding sequences. . J Gen Virol 81: 1699–1702. [CrossRef] [PubMed]
    [Google Scholar]
  31. Midgley R., Moffat K., Berryman S., Hawes P., Simpson J., Fullen D., Stephens D. J., Burman A., Jackson T..( 2013;). A role for endoplasmic reticulum exit sites in foot-and-mouth disease virus infection. . J Gen Virol 94: 2636–2646. [CrossRef] [PubMed]
    [Google Scholar]
  32. Monaghan P., Cook H., Jackson T., Ryan M., Wileman T..( 2004;). The ultrastructure of the developing replication site in foot-and-mouth disease virus-infected BHK-38 cells. . J Gen Virol 85: 933–946. [CrossRef] [PubMed]
    [Google Scholar]
  33. Moradpour D., Evans M. J., Gosert R., Yuan Z., Blum H. E., Goff S. P., Lindenbach B. D., Rice C. M..( 2004;). Insertion of green fluorescent protein into nonstructural protein 5A allows direct visualization of functional hepatitis C virus replication complexes. . J Virol 78: 7400–7409. [CrossRef] [PubMed]
    [Google Scholar]
  34. O'Donnell V. K., Pacheco J. M., Henry T. M., Mason P. W..( 2001;). Subcellular distribution of the foot-and-mouth disease virus 3A protein in cells infected with viruses encoding wild-type and bovine-attenuated forms of 3A. . Virology 287: 151–162. [CrossRef] [PubMed]
    [Google Scholar]
  35. Raubo P., Andrews D. M., McKelvie J. C., Robb G. R., Smith J. M., Swarbrick M. E., Waring M. J..( 2015;). Discovery of potent, selective small molecule inhibitors of alpha-subtype of type III phosphatidylinositol-4-kinase (PI4KIIIalpha). . Bioorg Med Chem Lett 25: 3189–3193. [CrossRef] [PubMed]
    [Google Scholar]
  36. Reiss S., Rebhan I., Backes P., Romero-Brey I., Erfle H., Matula P., Kaderali L., Poenisch M., Blankenburg H. et al.( 2011;). Recruitment and activation of a lipid kinase by hepatitis C virus NS5A is essential for integrity of the membranous replication compartment. . Cell Host Microbe 9: 32–45. [CrossRef] [PubMed]
    [Google Scholar]
  37. Ross-Thriepland D., Mankouri J., Harris M..( 2015;). Serine phosphorylation of the hepatitis C virus NS5A protein controls the establishment of replication complexes. . J Virol 89: 3123–3135. [CrossRef] [PubMed]
    [Google Scholar]
  38. Rutaganira F. U., Fowler M. L., McPhail J. A., Gelman M. A., Nguyen K., Xiong A., Dornan G. L., Tavshanjian B., Glenn J. S. et al.( 2016;). Design and structural characterization of potent and selective inhibitors of phosphatidylinositol 4 kinase IIIβ. . J Med Chem 59: 1830–1839. [CrossRef] [PubMed]
    [Google Scholar]
  39. Stewart H., Bartlett C., Ross-Thriepland D., Shaw J., Griffin S., Harris M..( 2015;). A novel method for the measurement of hepatitis C virus infectious titres using the IncuCyte ZOOM and its application to antiviral screening. . J Virol Methods 218: 59–65. [CrossRef] [PubMed]
    [Google Scholar]
  40. Thompson D., Muriel P., Russell D., Osborne P., Bromley A., Rowland M., Creigh-Tyte S., Brown C..( 2002;). Economic costs of the foot and mouth disease outbreak in the United Kingdom in 2001. . Rev Sci Tech 21: 675–687.[PubMed] [Crossref]
    [Google Scholar]
  41. Tsukiyama-Kohara K., Iizuka N., Kohara M., Nomoto A..( 1992;). Internal ribosome entry site within hepatitis C virus RNA. . J Virol 66: 1476–1483.[PubMed]
    [Google Scholar]
  42. Tulloch F., Pathania U., Luke G. A., Nicholson J., Stonehouse N. J., Rowlands D. J., Jackson T., Tuthill T., Haas J. et al.( 2014;). FMDV replicons encoding green fluorescent protein are replication competent. . J Virol Methods 209: 35–40. [CrossRef] [PubMed]
    [Google Scholar]
  43. Vázquez-Calvo A., Sobrino F., Martín-Acebes M. A..( 2012;). Plasma membrane phosphatidylinositol 4,5 bisphosphate is required for internalization of foot-and-mouth disease virus and vesicular stomatitis virus. . PLoS One 7: e45172. [CrossRef] [PubMed]
    [Google Scholar]
  44. Waring M. J., Andrews D. M., Faulder P. F., Flemington V., McKelvie J. C., Maman S., Preston M., Raubo P., Robb G. R. et al.( 2014;). Potent, selective small molecule inhibitors of type III phosphatidylinositol-4-kinase alpha- but not β-inhibit the phosphatidylinositol signaling cascade and cancer cell proliferation. . Chem Commun 50: 5388–5390. [CrossRef]
    [Google Scholar]
  45. Wyles D. L., Kaihara K. A., Korba B. E., Schooley R. T., Beadle J. R., Hostetler K. Y..( 2009;). The octadecyloxyethyl ester of (S)-9-[3-hydroxy-2-(phosphonomethoxy) propyl]adenine is a potent and selective inhibitor of hepatitis C virus replication in genotype 1A, 1B, and 2A replicons. . Antimicrob Agents Chemother 53: 2660–2662. [CrossRef] [PubMed]
    [Google Scholar]
  46. Zhang L., Hong Z., Lin W., Shao R. X., Goto K., Hsu V. W., Chung R. T..( 2012;). ARF1 and GBF1 generate a PI4P-enriched environment supportive of hepatitis C virus replication. . PLoS One 7: e32135. [CrossRef] [PubMed]
    [Google Scholar]
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